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DTT 2022; 1(1): 59-66

Published online July 31, 2022

https://doi.org/10.58502/DTT.22.002

Copyright © The Pharmaceutical Society of Korea.

Role of Aldehyde Dehydrogenase 3A1 in Cancer Progression

Sunyi Lee1 , Joohee Jung1,2

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1Duksung Innovative Drug Center, Duksung Women's University, Seoul, Korea
2College of Pharmacy, Duksung Women’s University, Seoul, Korea

Correspondence to:Joohee Jung, joohee@duksung.ac.kr

Received: April 29, 2022; Revised: June 9, 2022; Accepted: June 17, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Aldehyde dehydrogenase (ALDH) catalyzes the oxidation of aldehydes and is well known to detoxify exogenous and endogenous aldehydes. ALDH has also been reported to be associated with various biological processes and is found in several tissues and organs. ALDH is classified into three groups: class 1 (cytosolic), class 2 (mitochondrial), and class 3 (organ-specific). ALDH isoforms are found in all three classes. Particularly, many studies have reported the association of ALDH isoforms with cancer. In this review, we focus on ALDH3A1. Its expression is high in lung, gastric, colorectal, liver, pancreatic, ovarian, and prostate cancer but low in oral cancer. High ALDH3A1 expression increases cell growth, motility, and invasion, associated with tumor progression in a variety of cancer except for oral cancer. Furthermore, the induction of ALDH3A1 expression via the activation of nuclear factor erythroid 2-related factor-2 induces drug resistance. ALDH3A1 reduces aldehyde-induced toxicity in the oral cavity, but low ALDH3A1 expression promotes oral cancer progression. Modulation of ALDH3A1 is anticipated to be a good target for anticancer therapy.

KeywordsALDH3A1, cancer development, tumor progression, drug resistance, cancer therapy

Introduction

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Aldehyde dehydrogenase (ALDH) is an enzyme that oxidizes aldehydes to carboxylic acids (Marchitti et al. 2008). ALDH catalyzes the oxidation of aldehydes through NAD (P)+-dependent enzymatic activity and detoxifies and protects cells from reactive oxygen species (Vasiliou et al. 2004; Lei et al. 2019). It is involved in multiple cellular functions, such as cellular responses to proliferation, differentiation, and survival (Jackson et al. 2011). In addition, ALDH is important for the maintenance, differentiation, and normal development of stem cells, and its expression has been reported to promote chemical resistance and survival mechanisms of cancer stem cells (Clark and Palle 2016).

ALDH is classified into three groups: class 1 (cytosolic), class 2 (mitochondrial), and class 3 (organ-specific). ALDH isoforms are found in all three classes. It is a superfamily comprising 11 families and four subfamilies and consisting of 19 genes with distinct chromosomal locations (Table 1). ALDH mainly exists in the liver and is also distributed in various tissues (cornea, kidney, pancreas, stomach, etc.). It is localized in the cytoplasm, mitochondria, endoplasmic reticulum, and nucleus of the cells (Ibrahim et al. 2018).

Table 1 Chromosome location and substrates of human ALDH

ALDHChromosome locationSubstrate
ALDH1A19q21.13Retinal
ALDH1A215q22.1Retinal
ALDH1A315q26.3Retinal
ALDH1B19p11.1Retinal & acetaldehyde
ALDH1L13q21.210-Formyltetrahydrofolate
ALDH1L22q23.310-Formyltetrahydrofolate
ALDH212q24.2Acetaldehyde
ALDH3A117p11.2Aromatic & aliphatic aldehydes
ALDH3A217p11.2Fatty aldehydes
ALDH3B111q13.2Octanal
ALDH3B211q13.2Unknown
ALDH4A11p36.13Glutamate-γ-semialdehyde
ALDH5A16p22.2Succinate semialdehyde
ALDH6A114q24.3Malonate semialdehyde
ALDH7A15q31α-Amino adipic semialdehyde
ALDH8A16q23.2Retinal
ALDH9A11q23.1γ-Aminobutyraldehyde
ALDH16A119q13.33Unknown
ALDH18A110q24.3Glutamic- γ-semialdehyde

ALDH subtypes have been reported to have multiple functions in various cancers. In lung cancer, co-expression of ALDH (high) and CD44 (high) is a tumor-initiating cell marker that is associated with tumorigenicity and drug resistance (Liu et al. 2013). In prostate cancer, hypermethylation of ALDH1A2 promoter region is observed, restoration of ALDH1A2 expression inhibits cell growth (Kim et al. 2005). In the liver, ALDH2 helps the clearance of acetaldehyde and protects the development of hepatocellular carcinoma (HCC) (Jin et al. 2015), and its expression inhibits metastasis of HCC by the activation of AMP-activated protein kinase signaling pathway (Hou et al. 2017). In gastric cancer MKN-45 cells, suppression of ALDH1A1 reduces cell viability, migration, and invasion by the Wnt signaling pathway (Jiang et al. 2016). In gastric cancer, low ALDH3A2 expression is associated with poor overall survival (OS) (Yin et al. 2020). Understanding the context dependent role of ALDH is critical for the development of targeted cancer therapeutics.

ALDH3A1 is highly expressed in the mammalian cornea but not in the normal liver and its main function is to filter UV radiation through the cornea (Muzio et al. 2012). ALDH3A1 expression has been reported to be highly expressed in several tumors and stem cells, and its function is investigated. It is reported to regulate several cellular functions of normal and tumor cells, such as proliferation, differentiation, survival, and response to oxidative stress (Qu et al. 2020). However, the expression and function of ALDH3A1 are different depending on cancer types. Thus, we investigated the role of ALDH3A1 in various cancers and discussed its potential as a target in cancer therapy.

ALDH3A1 in Lung Cancer

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The expression level of ALDH3A1 is known to be high in patients with lung cancer. Lung cancer is classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Squamous cell cancer and adenocarcinoma have a higher expression of ALDH3A1 than that in SCLC. Thus, patients with NSCLC exhibit a higher expression level of ALDH3A1 than patients with SCLC (Patel et al. 2008). In addition, ALDH3A1 expression is induced by smoking, a carcinogen of lung cancer, and is reported to be significantly found in smokers from the large airway epithelium cells microarray data (Shahdoust et al. 2013).

In human NSCLC overexpressing ALDH3A1, the expression of epithelial to mesenchymal transition (EMT) markers such as vimentin, fibronectin, and zeb1 was increased. Pro-inflammatory and immunosuppressive mediators, such as nuclear factor-κB (NF-κB), prostaglandin E2, and interleukin-6 and -13 were also highly expressed. Consequentially, the expression of programmed cell death ligand-1 (PD-L1) on the surface of cancer cells was enhanced (Terzuoli et al. 2019). PD-L1 is known as a pro-tumorigenic factor and has shown to evade an anticancer response, indicating that it activates cell proliferation and promotes cancer progression (Han et al. 2020). ALDH3A1 has also been shown to contribute to the exosome-enhancing motility of recipient cells in the co-culture of exosomes extracted from irradiated lung cancer cells with other lung cancer cells (Wang et al. 2020a). Exosomes play an important role in intercellular communication as signaling mediators and are involved in tumor development (Milane et al. 2015).

ALDH3A1 promotes lung cancer progression and is regulated by several factors. B-cell lymphoma-2 associated athanogene 1 (Bag1) and p53 signaling pathways regulate ALDH3A1 expression (Lv et al. 2019; Fan et al. 2021). Induction of the orphan nuclear receptor (NROB1) increases ALDH3A1 expression, and proliferator-activated receptor γ suppresses its expression (Susaki et al. 2012).

ALDH3A1 is associated with drug resistance. ALDH3A1 gene is isolated as a differentially expressed gene from the paclitaxel-resistant lung adenocarcinoma A549-T cell line (Pu et al. 2020). RNAi-mediated knockdown of ALDH3A1 increases 4-hydroperoxy cyclophosphamide cytotoxicity in lung cancer A549 cells (Moreb et al. 2007). Inhibition of ALDH3A1 expression, as well as ALDH1A1 and ALDH1A3 by 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester (DIMATE, irreversible inhibitor of ALDH1 and ALDH3), overcomes specific drug resistance in NSCLC (Rebollido-Rios et al. 2020).

ALDH3A1 in Gastric Cancer

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Gastric cancer cell lines, MKN-45 and SGC-7901, with high expression of ALDH3A1 showed decreased levels of E-cadherin and increased levels of Snail and vimentin, indicating that ALDH3A1 is associated with the induction of EMT. Increased ALDH3A1 expression is correlated with dysplasia, as well as the grade, differentiation, lymph node metastasis, and staging of gastric cancer (Wu et al. 2016). As a result of cross-talk genes analysis through differentially expressed genes screening and protein-protein interaction network database, 8 genes are found to be shared in metabolism-related pathways. Among them, ALDH3A1 shows specific classification characteristics, indicating it could be a prognosis marker in patients with gastric cancer (Zhao et al. 2017).

In gastric cancer cells, ALDH3A1 converses fatty aldehydes occurred from lipid peroxidation into fatty acids and NADH, which is needed to produce ATP, indicating ALDH3A1 contributes to providing energy sources. Thus, ALDH3A1 depletion reduces ATP production and induces apoptosis (Lee et al. 2019).

ALDH3A1 in Colorectal Cancer

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ALDH3A1 level is low in normal rectal mucosa and uniquely expressed in the squamous epithelium of the anus at anorectal junctions (Chiang et al. 2012). ALDH3A1 activity is high in colon tumor tissues (Wroczyński et al. 2005). ALDH3A1 expression increases during the transition of epithelial cells from adhesive to round dissociative forms, indicating its association with cancer cell migration, invasion, and metastasis (Tang et al. 2014). In the comparison of the transcriptome of circulating tumor cells (CTC) derived from a patient with colon cancer and colorectal cancer cells, three stemness genes, five DNA repair-related genes, and seven genes contributing to energy metabolism are significantly expressed. ALDH3A1 is an overexpressed gene in the CTC of a patient with colon cancer, indicating that it plays a role in metastasis (Alix-Panabières et al. 2017).

In two- and three-dimension (D) KRAS-mutated colorectal cancer cells, 2-pyridine-4-yl methylene β-boswellic acid (PMBA), an inhibitor of NF-κB signaling pathway, shows a synergistic effect of 5-fluorouracil. ALDH1A2, 1A3, and 3A1 expressions increase in 3D more than in 2D colorectal cancer cells, but PMBA significantly decreases them, indicating NF-κB signaling pathway induces ALDH3A1expression (Qayum et al. 2022).

ALDH3A1 in Liver Cancer

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ALDH in 70% of poor differentiated human hepatocellular carcinoma (HCC) is strongly expressed (Agarwal et al. 1989; Shibuya et al. 1994). Particularly, ALDH3A1 expression is also high in HCC as well as in catenin beta 1-mutated hepatocellular adenomas and is associated with activation of the Wnt/β-catenin pathway. However, no correlation is observed between ALDH3A1 expression and OS (Calderaro et al. 2014).

ALDH3A1 as a metabolic gene is induced by polycyclic aromatic hydrocarbons such as β-naphthoflavone, benzo(a)pyrene quinones, and 2,3,7,8-tetrachlorodibenzo-p-dioxin known carcinogens (Burchiel et al. 2007; Muzio et al. 2012; Brauze et al. 2014). During hepatic tumorigenesis by these carcinogens, high ALDH3A1 expression and activity stimulates cell proliferation and resists drug- and aldehydes-induced toxicity (Dewa et al. 2008; Muzio et al. 2012). The promyelocytic leukemia protein also regulates ALDH3A1 expression, inducing resistance to arsenic trioxide in HCC therapy (Zhang et al. 2015). Benzyl isothiocyanate activates ALDH3A1 via the expression and activation of nuclear factor erythroid 2-related factor-2 (NRF2) (Liu et al. 2017). NRF2 is known to promote cancer cell proliferation and induce resistance to chemotherapy (Wu et al. 2019).

ALDH3A1 in Pancreatic Cancer

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NRF2, a transcriptional factor, regulates the expression of several downstream target genes such as phase I, II, and drug metabolizing enzymes. ALDH3A1, a downstream target gene of NRF2, is induced by NRF2 and is involved in xenobiotic detoxification (Wu et al. 2019). The reduction of ALDH3A1 expression by NRF2 depletion is sensitive to 5-FU (Duong et al. 2017) and gemcitabine (Matsumoto et al. 2021) in pancreatic cancer.

ALDH3A1 in Ovarian Cancer

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High-grade serous ovarian carcinoma shows a high expression of chromobox 2, which plays a role in cancer progression. Chromobox 2 knockdown decreases ALDH3A1 expression (Wheeler et al. 2018). High ALDH3A1 and ALDH1A3 expression is correlated with differentially hypomethylated genes and promotors in cisplatin-resistant ovarian yolk sac tumor cell line (NOY-1). Cisplatin-resistant NOY-1 cells involve the increase of migration, invasion and tumorigenicity (Schmidtova et al. 2020). Increasing ALDH3A1 expression correlated with cancer progression.

Pretreatment with napabucasin, a STAT3 inhibitor, inhibits chemoresistance of cancer stem cells by modulating ALDH3A1 expression (Schmidtova et al. 2020).

ALDH3A1 in Prostate Cancer

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ALDH3A1 expression is upregulated in DU145-derived prostate stem cells and metastatic tumors (Yan et al. 2014). In prostate cancer progression, putative castration-resistant stem-like cells (CRSC) are associated with aggressiveness. Eight genes including ALDH1A1, 1A3, and 3A1 are observed as CRSC markers, ALDH overexpressed in prostate cancer tissues (Federer-Gsponer et al. 2020).

Cabazitaxel-resistant prostate cancer cells increase ALDH3A1 expression. However, shikonin enhanced the sensitivity of cabazitaxel by increasing reactive oxygen species and inhibits ALDH3A1 expression (Wang et al. 2020b). Inhibition of ALDH by (diethylamino) benzaldehyde increases chemosensitivity (Ibrahim et al. 2022).

ALDH3A1 in Oral Cancer

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ALDH3A1 expression is often high in minor salivary gland, tonsil and oral epithelium and its activation in the oral cavity reduces aldehyde accumulation, indicating that salivary ALDH3A1 protects against toxicants including cigarette smoke (Jang et al. 2014). ALDH3A1 activity in the saliva, cancerous, and bordering tissues of patients with oral cancers was found to be lower than that in healthy volunteers. It is associated with a higher incidence of lymph node metastasis and a poor overall survival rate (Giebułtowicz et al. 2013).

Restoration of ALDH3A1 expression inhibits proliferation, migration, and invasion of oral squamous cell carcinoma (Qu et al. 2020). Low ALDH3A1 expression levels have been shown to promote EMT in oral cancers (Vallina et al. 2021). High ALDH3A1 expression inhibits tumor-associated macrophages via the IL-6/STAT 3 signaling pathway (Qu et al. 2020) and mitochondrial reactive oxygen species, indicating that it inhibits cancer-related inflammation and suppresses tumor progression (Wang et al. 2022).

Sulforaphane (Alam et al. 2016), thymoquinone (Laskar et al. 2017), and d-limonene (Saiki et al. 2018) induce human salivary ALDH activity, suggesting it decreases the risk of oral cancer development.

Conclusion

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This review discusses the role of ALDH3A1 in various cancers and the factors regulating ALDH3A1 expression. ALDH3A1 expression was high in lung, gastric, colorectal, liver, pancreatic, ovarian, and prostate cancers, but low in oral cancer (Table 2). As shown in Fig. 1, up-regulation of ALDH3A1 expression is associated with NROB1, NRF1, chromobox 2, and Bag1/p53 pathway, whereas ALDH3A1 expression is down-regulated by PPARγ. The mechanism and functions of ALDH3A1 are summarized in Fig. 1. ALDH3A1 promotes cell proliferation through the production of energy sources via fatty acid oxidation and enhances tumor growth, invasion, and metastasis through various pathways. Furthermore, high ALDH3A1 expression induces drug resistance. ALDH3A1 inhibitors enhance the sensitivity of anticancer drugs and suppressed cancer progression (Parajuli et al. 2014a; Parajuli et al. 2014b; Chen et al. 2015; Dinavahi et al. 2019), whereas ALDH3A1 activators protect oral cancer progression and the enzyme function from radiation (Xiao et al. 2013) (Fig. 2). Since modulation of ALDH3A1 impedes cancer progression, it could be a suitable target for anticancer therapeutic agents.

Table 2 Expression and role of ALDH3A1 in various cancers

ExpressionType of cancerRole of ALDH3A1References
UpLung cancer• Increase of EMT markers, proinflammatory immunosuppressive mediates, PD-L1• Terzuoli et al. 2019
• Enhancement of exosomes• Wang et al. 2020a
• Induction of drug resistance• Moreb et al. 2007;Pu et al. 2020
Gastric cancer• Decrease of E-cadherin and increase of EMT markers• Wu et al. 2016
• Provision of energy source (ATP)• Lee et al. 2019
Colorectal cancer• Transition from adhesive epithelial type to round dissociation type• Tang et al. 2014
• Regulation of energy metabolism in circulating tumor cells• Alix-Panabières et al. 2017
Liver cancer• Activation of the Wnt/β-Catenin pathway• Calderaro et al. 2014
• Induction of drug resistance• Zhang et al. 2015
Pancreatic cancer• Pancreatic cancer stem-like cell biomarker• Marcato et al. 2011
• Induction of drug resistance• Duong et al. 2017; Matsumoto et al. 2021
Ovarian cancer• Correlation of chromobox 2 expression• Wheeler et al. 2018
• Induction of drug resistance• Schmidtova et al. 2020
Prostate cancer• Induction of drug resistance• Wang et al. 2020b; Ibrahim et al. 2022
DownOral cancer• Promotion of EMT• Vallina et al. 2021
• Increase of tumor-associated macrophages and reactive oxygen species• Qu et al. 2020

Figure 1.Regulation and function of ALDH3A1 associated with cancer progression and drug resistance. ALDH3A1 expression is induced by NROB1, NRF1, chromobox 2, and Bag1/p53 pathway, and decreased by PPARγ. ALDH3A1 produces energy sources (e.g., ATP) through fatty acid oxidation, supporting cancer cell proliferation. ALDH3A1 activates Wnt/β-catenin, NF-kB signaling, and IL-6/STAT signaling pathway, PD-L1 expression, and exosome-enhancing motility, inducing cell proliferation and evading an anticancer response. High ALDH3A1 expression increased EMT markers, enhancing metastasis.

Figure 2.Regulation of ALDH3A1 for cancer therapy. ALDH3A1 inhibitors decrease cancer progression and sensitize to anticancer drugs in various ALDH3A1 overexpressed cancer cells. ALDH3A1 activators protect oral cancer progression. (DIMATE, 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester; PMBA, 2-pyridine-4-yl methylene β-boswellic acid).

ALDH3A1 in Lung Cancer

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The expression level of ALDH3A1 is known to be high in patients with lung cancer. Lung cancer is classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Squamous cell cancer and adenocarcinoma have a higher expression of ALDH3A1 than that in SCLC. Thus, patients with NSCLC exhibit a higher expression level of ALDH3A1 than patients with SCLC (Patel et al. 2008). In addition, ALDH3A1 expression is induced by smoking, a carcinogen of lung cancer, and is reported to be significantly found in smokers from the large airway epithelium cells microarray data (Shahdoust et al. 2013).

In human NSCLC overexpressing ALDH3A1, the expression of epithelial to mesenchymal transition (EMT) markers such as vimentin, fibronectin, and zeb1 was increased. Pro-inflammatory and immunosuppressive mediators, such as nuclear factor-κB (NF-κB), prostaglandin E2, and interleukin-6 and -13 were also highly expressed. Consequentially, the expression of programmed cell death ligand-1 (PD-L1) on the surface of cancer cells was enhanced (Terzuoli et al. 2019). PD-L1 is known as a pro-tumorigenic factor and has shown to evade an anticancer response, indicating that it activates cell proliferation and promotes cancer progression (Han et al. 2020). ALDH3A1 has also been shown to contribute to the exosome-enhancing motility of recipient cells in the co-culture of exosomes extracted from irradiated lung cancer cells with other lung cancer cells (Wang et al. 2020a). Exosomes play an important role in intercellular communication as signaling mediators and are involved in tumor development (Milane et al. 2015).

ALDH3A1 promotes lung cancer progression and is regulated by several factors. B-cell lymphoma-2 associated athanogene 1 (Bag1) and p53 signaling pathways regulate ALDH3A1 expression (Lv et al. 2019; Fan et al. 2021). Induction of the orphan nuclear receptor (NROB1) increases ALDH3A1 expression, and proliferator-activated receptor γ suppresses its expression (Susaki et al. 2012).

ALDH3A1 is associated with drug resistance. ALDH3A1 gene is isolated as a differentially expressed gene from the paclitaxel-resistant lung adenocarcinoma A549-T cell line (Pu et al. 2020). RNAi-mediated knockdown of ALDH3A1 increases 4-hydroperoxy cyclophosphamide cytotoxicity in lung cancer A549 cells (Moreb et al. 2007). Inhibition of ALDH3A1 expression, as well as ALDH1A1 and ALDH1A3 by 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester (DIMATE, irreversible inhibitor of ALDH1 and ALDH3), overcomes specific drug resistance in NSCLC (Rebollido-Rios et al. 2020).

Acknowledgements

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This study was supported by the Basic Science Research Program through the NRF funded by the Ministry of Education (2021R1A6A3A01086368), the NRF grant funded by the Korean government, MSIT (2021R1A2C200453511), and the Priority Research Centers Program through the NRF funded by the Ministry of Education, Science and Technology (2016R1A6A1A03007648).

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Article

Review

DTT 2022; 1(1): 59-66

Published online July 31, 2022 https://doi.org/10.58502/DTT.22.002

Copyright © The Pharmaceutical Society of Korea.

Role of Aldehyde Dehydrogenase 3A1 in Cancer Progression

Sunyi Lee1 , Joohee Jung1,2

1Duksung Innovative Drug Center, Duksung Women's University, Seoul, Korea
2College of Pharmacy, Duksung Women’s University, Seoul, Korea

Correspondence to:Joohee Jung, joohee@duksung.ac.kr

Received: April 29, 2022; Revised: June 9, 2022; Accepted: June 17, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Aldehyde dehydrogenase (ALDH) catalyzes the oxidation of aldehydes and is well known to detoxify exogenous and endogenous aldehydes. ALDH has also been reported to be associated with various biological processes and is found in several tissues and organs. ALDH is classified into three groups: class 1 (cytosolic), class 2 (mitochondrial), and class 3 (organ-specific). ALDH isoforms are found in all three classes. Particularly, many studies have reported the association of ALDH isoforms with cancer. In this review, we focus on ALDH3A1. Its expression is high in lung, gastric, colorectal, liver, pancreatic, ovarian, and prostate cancer but low in oral cancer. High ALDH3A1 expression increases cell growth, motility, and invasion, associated with tumor progression in a variety of cancer except for oral cancer. Furthermore, the induction of ALDH3A1 expression via the activation of nuclear factor erythroid 2-related factor-2 induces drug resistance. ALDH3A1 reduces aldehyde-induced toxicity in the oral cavity, but low ALDH3A1 expression promotes oral cancer progression. Modulation of ALDH3A1 is anticipated to be a good target for anticancer therapy.

Keywords: ALDH3A1, cancer development, tumor progression, drug resistance, cancer therapy

Introduction

Aldehyde dehydrogenase (ALDH) is an enzyme that oxidizes aldehydes to carboxylic acids (Marchitti et al. 2008). ALDH catalyzes the oxidation of aldehydes through NAD (P)+-dependent enzymatic activity and detoxifies and protects cells from reactive oxygen species (Vasiliou et al. 2004; Lei et al. 2019). It is involved in multiple cellular functions, such as cellular responses to proliferation, differentiation, and survival (Jackson et al. 2011). In addition, ALDH is important for the maintenance, differentiation, and normal development of stem cells, and its expression has been reported to promote chemical resistance and survival mechanisms of cancer stem cells (Clark and Palle 2016).

ALDH is classified into three groups: class 1 (cytosolic), class 2 (mitochondrial), and class 3 (organ-specific). ALDH isoforms are found in all three classes. It is a superfamily comprising 11 families and four subfamilies and consisting of 19 genes with distinct chromosomal locations (Table 1). ALDH mainly exists in the liver and is also distributed in various tissues (cornea, kidney, pancreas, stomach, etc.). It is localized in the cytoplasm, mitochondria, endoplasmic reticulum, and nucleus of the cells (Ibrahim et al. 2018).

Table 1 . Chromosome location and substrates of human ALDH.

ALDHChromosome locationSubstrate
ALDH1A19q21.13Retinal
ALDH1A215q22.1Retinal
ALDH1A315q26.3Retinal
ALDH1B19p11.1Retinal & acetaldehyde
ALDH1L13q21.210-Formyltetrahydrofolate
ALDH1L22q23.310-Formyltetrahydrofolate
ALDH212q24.2Acetaldehyde
ALDH3A117p11.2Aromatic & aliphatic aldehydes
ALDH3A217p11.2Fatty aldehydes
ALDH3B111q13.2Octanal
ALDH3B211q13.2Unknown
ALDH4A11p36.13Glutamate-γ-semialdehyde
ALDH5A16p22.2Succinate semialdehyde
ALDH6A114q24.3Malonate semialdehyde
ALDH7A15q31α-Amino adipic semialdehyde
ALDH8A16q23.2Retinal
ALDH9A11q23.1γ-Aminobutyraldehyde
ALDH16A119q13.33Unknown
ALDH18A110q24.3Glutamic- γ-semialdehyde


ALDH subtypes have been reported to have multiple functions in various cancers. In lung cancer, co-expression of ALDH (high) and CD44 (high) is a tumor-initiating cell marker that is associated with tumorigenicity and drug resistance (Liu et al. 2013). In prostate cancer, hypermethylation of ALDH1A2 promoter region is observed, restoration of ALDH1A2 expression inhibits cell growth (Kim et al. 2005). In the liver, ALDH2 helps the clearance of acetaldehyde and protects the development of hepatocellular carcinoma (HCC) (Jin et al. 2015), and its expression inhibits metastasis of HCC by the activation of AMP-activated protein kinase signaling pathway (Hou et al. 2017). In gastric cancer MKN-45 cells, suppression of ALDH1A1 reduces cell viability, migration, and invasion by the Wnt signaling pathway (Jiang et al. 2016). In gastric cancer, low ALDH3A2 expression is associated with poor overall survival (OS) (Yin et al. 2020). Understanding the context dependent role of ALDH is critical for the development of targeted cancer therapeutics.

ALDH3A1 is highly expressed in the mammalian cornea but not in the normal liver and its main function is to filter UV radiation through the cornea (Muzio et al. 2012). ALDH3A1 expression has been reported to be highly expressed in several tumors and stem cells, and its function is investigated. It is reported to regulate several cellular functions of normal and tumor cells, such as proliferation, differentiation, survival, and response to oxidative stress (Qu et al. 2020). However, the expression and function of ALDH3A1 are different depending on cancer types. Thus, we investigated the role of ALDH3A1 in various cancers and discussed its potential as a target in cancer therapy.

ALDH3A1 in Lung Cancer

The expression level of ALDH3A1 is known to be high in patients with lung cancer. Lung cancer is classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Squamous cell cancer and adenocarcinoma have a higher expression of ALDH3A1 than that in SCLC. Thus, patients with NSCLC exhibit a higher expression level of ALDH3A1 than patients with SCLC (Patel et al. 2008). In addition, ALDH3A1 expression is induced by smoking, a carcinogen of lung cancer, and is reported to be significantly found in smokers from the large airway epithelium cells microarray data (Shahdoust et al. 2013).

In human NSCLC overexpressing ALDH3A1, the expression of epithelial to mesenchymal transition (EMT) markers such as vimentin, fibronectin, and zeb1 was increased. Pro-inflammatory and immunosuppressive mediators, such as nuclear factor-κB (NF-κB), prostaglandin E2, and interleukin-6 and -13 were also highly expressed. Consequentially, the expression of programmed cell death ligand-1 (PD-L1) on the surface of cancer cells was enhanced (Terzuoli et al. 2019). PD-L1 is known as a pro-tumorigenic factor and has shown to evade an anticancer response, indicating that it activates cell proliferation and promotes cancer progression (Han et al. 2020). ALDH3A1 has also been shown to contribute to the exosome-enhancing motility of recipient cells in the co-culture of exosomes extracted from irradiated lung cancer cells with other lung cancer cells (Wang et al. 2020a). Exosomes play an important role in intercellular communication as signaling mediators and are involved in tumor development (Milane et al. 2015).

ALDH3A1 promotes lung cancer progression and is regulated by several factors. B-cell lymphoma-2 associated athanogene 1 (Bag1) and p53 signaling pathways regulate ALDH3A1 expression (Lv et al. 2019; Fan et al. 2021). Induction of the orphan nuclear receptor (NROB1) increases ALDH3A1 expression, and proliferator-activated receptor γ suppresses its expression (Susaki et al. 2012).

ALDH3A1 is associated with drug resistance. ALDH3A1 gene is isolated as a differentially expressed gene from the paclitaxel-resistant lung adenocarcinoma A549-T cell line (Pu et al. 2020). RNAi-mediated knockdown of ALDH3A1 increases 4-hydroperoxy cyclophosphamide cytotoxicity in lung cancer A549 cells (Moreb et al. 2007). Inhibition of ALDH3A1 expression, as well as ALDH1A1 and ALDH1A3 by 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester (DIMATE, irreversible inhibitor of ALDH1 and ALDH3), overcomes specific drug resistance in NSCLC (Rebollido-Rios et al. 2020).

ALDH3A1 in Gastric Cancer

Gastric cancer cell lines, MKN-45 and SGC-7901, with high expression of ALDH3A1 showed decreased levels of E-cadherin and increased levels of Snail and vimentin, indicating that ALDH3A1 is associated with the induction of EMT. Increased ALDH3A1 expression is correlated with dysplasia, as well as the grade, differentiation, lymph node metastasis, and staging of gastric cancer (Wu et al. 2016). As a result of cross-talk genes analysis through differentially expressed genes screening and protein-protein interaction network database, 8 genes are found to be shared in metabolism-related pathways. Among them, ALDH3A1 shows specific classification characteristics, indicating it could be a prognosis marker in patients with gastric cancer (Zhao et al. 2017).

In gastric cancer cells, ALDH3A1 converses fatty aldehydes occurred from lipid peroxidation into fatty acids and NADH, which is needed to produce ATP, indicating ALDH3A1 contributes to providing energy sources. Thus, ALDH3A1 depletion reduces ATP production and induces apoptosis (Lee et al. 2019).

ALDH3A1 in Colorectal Cancer

ALDH3A1 level is low in normal rectal mucosa and uniquely expressed in the squamous epithelium of the anus at anorectal junctions (Chiang et al. 2012). ALDH3A1 activity is high in colon tumor tissues (Wroczyński et al. 2005). ALDH3A1 expression increases during the transition of epithelial cells from adhesive to round dissociative forms, indicating its association with cancer cell migration, invasion, and metastasis (Tang et al. 2014). In the comparison of the transcriptome of circulating tumor cells (CTC) derived from a patient with colon cancer and colorectal cancer cells, three stemness genes, five DNA repair-related genes, and seven genes contributing to energy metabolism are significantly expressed. ALDH3A1 is an overexpressed gene in the CTC of a patient with colon cancer, indicating that it plays a role in metastasis (Alix-Panabières et al. 2017).

In two- and three-dimension (D) KRAS-mutated colorectal cancer cells, 2-pyridine-4-yl methylene β-boswellic acid (PMBA), an inhibitor of NF-κB signaling pathway, shows a synergistic effect of 5-fluorouracil. ALDH1A2, 1A3, and 3A1 expressions increase in 3D more than in 2D colorectal cancer cells, but PMBA significantly decreases them, indicating NF-κB signaling pathway induces ALDH3A1expression (Qayum et al. 2022).

ALDH3A1 in Liver Cancer

ALDH in 70% of poor differentiated human hepatocellular carcinoma (HCC) is strongly expressed (Agarwal et al. 1989; Shibuya et al. 1994). Particularly, ALDH3A1 expression is also high in HCC as well as in catenin beta 1-mutated hepatocellular adenomas and is associated with activation of the Wnt/β-catenin pathway. However, no correlation is observed between ALDH3A1 expression and OS (Calderaro et al. 2014).

ALDH3A1 as a metabolic gene is induced by polycyclic aromatic hydrocarbons such as β-naphthoflavone, benzo(a)pyrene quinones, and 2,3,7,8-tetrachlorodibenzo-p-dioxin known carcinogens (Burchiel et al. 2007; Muzio et al. 2012; Brauze et al. 2014). During hepatic tumorigenesis by these carcinogens, high ALDH3A1 expression and activity stimulates cell proliferation and resists drug- and aldehydes-induced toxicity (Dewa et al. 2008; Muzio et al. 2012). The promyelocytic leukemia protein also regulates ALDH3A1 expression, inducing resistance to arsenic trioxide in HCC therapy (Zhang et al. 2015). Benzyl isothiocyanate activates ALDH3A1 via the expression and activation of nuclear factor erythroid 2-related factor-2 (NRF2) (Liu et al. 2017). NRF2 is known to promote cancer cell proliferation and induce resistance to chemotherapy (Wu et al. 2019).

ALDH3A1 in Pancreatic Cancer

NRF2, a transcriptional factor, regulates the expression of several downstream target genes such as phase I, II, and drug metabolizing enzymes. ALDH3A1, a downstream target gene of NRF2, is induced by NRF2 and is involved in xenobiotic detoxification (Wu et al. 2019). The reduction of ALDH3A1 expression by NRF2 depletion is sensitive to 5-FU (Duong et al. 2017) and gemcitabine (Matsumoto et al. 2021) in pancreatic cancer.

ALDH3A1 in Ovarian Cancer

High-grade serous ovarian carcinoma shows a high expression of chromobox 2, which plays a role in cancer progression. Chromobox 2 knockdown decreases ALDH3A1 expression (Wheeler et al. 2018). High ALDH3A1 and ALDH1A3 expression is correlated with differentially hypomethylated genes and promotors in cisplatin-resistant ovarian yolk sac tumor cell line (NOY-1). Cisplatin-resistant NOY-1 cells involve the increase of migration, invasion and tumorigenicity (Schmidtova et al. 2020). Increasing ALDH3A1 expression correlated with cancer progression.

Pretreatment with napabucasin, a STAT3 inhibitor, inhibits chemoresistance of cancer stem cells by modulating ALDH3A1 expression (Schmidtova et al. 2020).

ALDH3A1 in Prostate Cancer

ALDH3A1 expression is upregulated in DU145-derived prostate stem cells and metastatic tumors (Yan et al. 2014). In prostate cancer progression, putative castration-resistant stem-like cells (CRSC) are associated with aggressiveness. Eight genes including ALDH1A1, 1A3, and 3A1 are observed as CRSC markers, ALDH overexpressed in prostate cancer tissues (Federer-Gsponer et al. 2020).

Cabazitaxel-resistant prostate cancer cells increase ALDH3A1 expression. However, shikonin enhanced the sensitivity of cabazitaxel by increasing reactive oxygen species and inhibits ALDH3A1 expression (Wang et al. 2020b). Inhibition of ALDH by (diethylamino) benzaldehyde increases chemosensitivity (Ibrahim et al. 2022).

ALDH3A1 in Oral Cancer

ALDH3A1 expression is often high in minor salivary gland, tonsil and oral epithelium and its activation in the oral cavity reduces aldehyde accumulation, indicating that salivary ALDH3A1 protects against toxicants including cigarette smoke (Jang et al. 2014). ALDH3A1 activity in the saliva, cancerous, and bordering tissues of patients with oral cancers was found to be lower than that in healthy volunteers. It is associated with a higher incidence of lymph node metastasis and a poor overall survival rate (Giebułtowicz et al. 2013).

Restoration of ALDH3A1 expression inhibits proliferation, migration, and invasion of oral squamous cell carcinoma (Qu et al. 2020). Low ALDH3A1 expression levels have been shown to promote EMT in oral cancers (Vallina et al. 2021). High ALDH3A1 expression inhibits tumor-associated macrophages via the IL-6/STAT 3 signaling pathway (Qu et al. 2020) and mitochondrial reactive oxygen species, indicating that it inhibits cancer-related inflammation and suppresses tumor progression (Wang et al. 2022).

Sulforaphane (Alam et al. 2016), thymoquinone (Laskar et al. 2017), and d-limonene (Saiki et al. 2018) induce human salivary ALDH activity, suggesting it decreases the risk of oral cancer development.

Conclusion

This review discusses the role of ALDH3A1 in various cancers and the factors regulating ALDH3A1 expression. ALDH3A1 expression was high in lung, gastric, colorectal, liver, pancreatic, ovarian, and prostate cancers, but low in oral cancer (Table 2). As shown in Fig. 1, up-regulation of ALDH3A1 expression is associated with NROB1, NRF1, chromobox 2, and Bag1/p53 pathway, whereas ALDH3A1 expression is down-regulated by PPARγ. The mechanism and functions of ALDH3A1 are summarized in Fig. 1. ALDH3A1 promotes cell proliferation through the production of energy sources via fatty acid oxidation and enhances tumor growth, invasion, and metastasis through various pathways. Furthermore, high ALDH3A1 expression induces drug resistance. ALDH3A1 inhibitors enhance the sensitivity of anticancer drugs and suppressed cancer progression (Parajuli et al. 2014a; Parajuli et al. 2014b; Chen et al. 2015; Dinavahi et al. 2019), whereas ALDH3A1 activators protect oral cancer progression and the enzyme function from radiation (Xiao et al. 2013) (Fig. 2). Since modulation of ALDH3A1 impedes cancer progression, it could be a suitable target for anticancer therapeutic agents.

Table 2 . Expression and role of ALDH3A1 in various cancers.

ExpressionType of cancerRole of ALDH3A1References
UpLung cancer• Increase of EMT markers, proinflammatory immunosuppressive mediates, PD-L1• Terzuoli et al. 2019
• Enhancement of exosomes• Wang et al. 2020a
• Induction of drug resistance• Moreb et al. 2007;Pu et al. 2020
Gastric cancer• Decrease of E-cadherin and increase of EMT markers• Wu et al. 2016
• Provision of energy source (ATP)• Lee et al. 2019
Colorectal cancer• Transition from adhesive epithelial type to round dissociation type• Tang et al. 2014
• Regulation of energy metabolism in circulating tumor cells• Alix-Panabières et al. 2017
Liver cancer• Activation of the Wnt/β-Catenin pathway• Calderaro et al. 2014
• Induction of drug resistance• Zhang et al. 2015
Pancreatic cancer• Pancreatic cancer stem-like cell biomarker• Marcato et al. 2011
• Induction of drug resistance• Duong et al. 2017; Matsumoto et al. 2021
Ovarian cancer• Correlation of chromobox 2 expression• Wheeler et al. 2018
• Induction of drug resistance• Schmidtova et al. 2020
Prostate cancer• Induction of drug resistance• Wang et al. 2020b; Ibrahim et al. 2022
DownOral cancer• Promotion of EMT• Vallina et al. 2021
• Increase of tumor-associated macrophages and reactive oxygen species• Qu et al. 2020


Figure 1. Regulation and function of ALDH3A1 associated with cancer progression and drug resistance. ALDH3A1 expression is induced by NROB1, NRF1, chromobox 2, and Bag1/p53 pathway, and decreased by PPARγ. ALDH3A1 produces energy sources (e.g., ATP) through fatty acid oxidation, supporting cancer cell proliferation. ALDH3A1 activates Wnt/β-catenin, NF-kB signaling, and IL-6/STAT signaling pathway, PD-L1 expression, and exosome-enhancing motility, inducing cell proliferation and evading an anticancer response. High ALDH3A1 expression increased EMT markers, enhancing metastasis.

Figure 2. Regulation of ALDH3A1 for cancer therapy. ALDH3A1 inhibitors decrease cancer progression and sensitize to anticancer drugs in various ALDH3A1 overexpressed cancer cells. ALDH3A1 activators protect oral cancer progression. (DIMATE, 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester; PMBA, 2-pyridine-4-yl methylene β-boswellic acid).

ALDH3A1 in Lung Cancer

The expression level of ALDH3A1 is known to be high in patients with lung cancer. Lung cancer is classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Squamous cell cancer and adenocarcinoma have a higher expression of ALDH3A1 than that in SCLC. Thus, patients with NSCLC exhibit a higher expression level of ALDH3A1 than patients with SCLC (Patel et al. 2008). In addition, ALDH3A1 expression is induced by smoking, a carcinogen of lung cancer, and is reported to be significantly found in smokers from the large airway epithelium cells microarray data (Shahdoust et al. 2013).

In human NSCLC overexpressing ALDH3A1, the expression of epithelial to mesenchymal transition (EMT) markers such as vimentin, fibronectin, and zeb1 was increased. Pro-inflammatory and immunosuppressive mediators, such as nuclear factor-κB (NF-κB), prostaglandin E2, and interleukin-6 and -13 were also highly expressed. Consequentially, the expression of programmed cell death ligand-1 (PD-L1) on the surface of cancer cells was enhanced (Terzuoli et al. 2019). PD-L1 is known as a pro-tumorigenic factor and has shown to evade an anticancer response, indicating that it activates cell proliferation and promotes cancer progression (Han et al. 2020). ALDH3A1 has also been shown to contribute to the exosome-enhancing motility of recipient cells in the co-culture of exosomes extracted from irradiated lung cancer cells with other lung cancer cells (Wang et al. 2020a). Exosomes play an important role in intercellular communication as signaling mediators and are involved in tumor development (Milane et al. 2015).

ALDH3A1 promotes lung cancer progression and is regulated by several factors. B-cell lymphoma-2 associated athanogene 1 (Bag1) and p53 signaling pathways regulate ALDH3A1 expression (Lv et al. 2019; Fan et al. 2021). Induction of the orphan nuclear receptor (NROB1) increases ALDH3A1 expression, and proliferator-activated receptor γ suppresses its expression (Susaki et al. 2012).

ALDH3A1 is associated with drug resistance. ALDH3A1 gene is isolated as a differentially expressed gene from the paclitaxel-resistant lung adenocarcinoma A549-T cell line (Pu et al. 2020). RNAi-mediated knockdown of ALDH3A1 increases 4-hydroperoxy cyclophosphamide cytotoxicity in lung cancer A549 cells (Moreb et al. 2007). Inhibition of ALDH3A1 expression, as well as ALDH1A1 and ALDH1A3 by 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester (DIMATE, irreversible inhibitor of ALDH1 and ALDH3), overcomes specific drug resistance in NSCLC (Rebollido-Rios et al. 2020).

Acknowledgements

This study was supported by the Basic Science Research Program through the NRF funded by the Ministry of Education (2021R1A6A3A01086368), the NRF grant funded by the Korean government, MSIT (2021R1A2C200453511), and the Priority Research Centers Program through the NRF funded by the Ministry of Education, Science and Technology (2016R1A6A1A03007648).

Fig 1.

Download
Figure 1.Regulation and function of ALDH3A1 associated with cancer progression and drug resistance. ALDH3A1 expression is induced by NROB1, NRF1, chromobox 2, and Bag1/p53 pathway, and decreased by PPARγ. ALDH3A1 produces energy sources (e.g., ATP) through fatty acid oxidation, supporting cancer cell proliferation. ALDH3A1 activates Wnt/β-catenin, NF-kB signaling, and IL-6/STAT signaling pathway, PD-L1 expression, and exosome-enhancing motility, inducing cell proliferation and evading an anticancer response. High ALDH3A1 expression increased EMT markers, enhancing metastasis.
Drug Targets and Therapeutics 2022; 1: 59-66https://doi.org/10.58502/DTT.22.002

Fig 2.

Download
Figure 2.Regulation of ALDH3A1 for cancer therapy. ALDH3A1 inhibitors decrease cancer progression and sensitize to anticancer drugs in various ALDH3A1 overexpressed cancer cells. ALDH3A1 activators protect oral cancer progression. (DIMATE, 4-dimethylamino-4-methylpent-2-ynthioic acid S-methylester; PMBA, 2-pyridine-4-yl methylene β-boswellic acid).
Drug Targets and Therapeutics 2022; 1: 59-66https://doi.org/10.58502/DTT.22.002

Table 1 Chromosome location and substrates of human ALDH

ALDHChromosome locationSubstrate
ALDH1A19q21.13Retinal
ALDH1A215q22.1Retinal
ALDH1A315q26.3Retinal
ALDH1B19p11.1Retinal & acetaldehyde
ALDH1L13q21.210-Formyltetrahydrofolate
ALDH1L22q23.310-Formyltetrahydrofolate
ALDH212q24.2Acetaldehyde
ALDH3A117p11.2Aromatic & aliphatic aldehydes
ALDH3A217p11.2Fatty aldehydes
ALDH3B111q13.2Octanal
ALDH3B211q13.2Unknown
ALDH4A11p36.13Glutamate-γ-semialdehyde
ALDH5A16p22.2Succinate semialdehyde
ALDH6A114q24.3Malonate semialdehyde
ALDH7A15q31α-Amino adipic semialdehyde
ALDH8A16q23.2Retinal
ALDH9A11q23.1γ-Aminobutyraldehyde
ALDH16A119q13.33Unknown
ALDH18A110q24.3Glutamic- γ-semialdehyde

Table 2 Expression and role of ALDH3A1 in various cancers

ExpressionType of cancerRole of ALDH3A1References
UpLung cancer• Increase of EMT markers, proinflammatory immunosuppressive mediates, PD-L1• Terzuoli et al. 2019
• Enhancement of exosomes• Wang et al. 2020a
• Induction of drug resistance• Moreb et al. 2007;Pu et al. 2020
Gastric cancer• Decrease of E-cadherin and increase of EMT markers• Wu et al. 2016
• Provision of energy source (ATP)• Lee et al. 2019
Colorectal cancer• Transition from adhesive epithelial type to round dissociation type• Tang et al. 2014
• Regulation of energy metabolism in circulating tumor cells• Alix-Panabières et al. 2017
Liver cancer• Activation of the Wnt/β-Catenin pathway• Calderaro et al. 2014
• Induction of drug resistance• Zhang et al. 2015
Pancreatic cancer• Pancreatic cancer stem-like cell biomarker• Marcato et al. 2011
• Induction of drug resistance• Duong et al. 2017; Matsumoto et al. 2021
Ovarian cancer• Correlation of chromobox 2 expression• Wheeler et al. 2018
• Induction of drug resistance• Schmidtova et al. 2020
Prostate cancer• Induction of drug resistance• Wang et al. 2020b; Ibrahim et al. 2022
DownOral cancer• Promotion of EMT• Vallina et al. 2021
• Increase of tumor-associated macrophages and reactive oxygen species• Qu et al. 2020

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