Aldehyde Dehydrogenase-1A1 (ALDH1A1): The Novel Regulator of Chemoresistance in Pancreatic Cancer Cells

Abstract

Aldehyde dehydrogenase-1A1 (ALDH1A1), a member of a superfamily of 19 isozymes, exhibits various biological functions and is involved in several important physiological and pathological processes, including those associated with various diseases including cancers such as pancreatic cancer. Chemotherapy is one of the most important strategies for the treatment of pancreatic cancer; however, the chemoresistance exhibited by pancreatic cancer cells is a leading cause of chemotherapy failure. It has been reported that overexpression of ALDH1A1 significantly correlates with poor prognosis and tumor aggressiveness, and is clinically associated with chemoresistance. Additionally, ALDH1A1 may serve as a novel regulator for the diagnosis and prognosis of cancer resistance. In particular, ALDH1A1 can promote cancer progression by facilitating the manifestation of cancer stem cell properties. However, the molecular mechanism by which ALDH1A1 clinically regulates the development of chemoresistance, and its role in prognosis and cancer stem cells, including pancreatic cancer stem cells, remain unclear. Therefore, the current review aims to summarize the clinical functions of ALDH1A1 as a novel regulator of chemoresistance, prognosis, and cancer stem cell development in pancreatic cancer.

Keywords

aldehyde dehydrogenase-1A1 chemoresistance pancreatic cancer cells cancer drug resistance cancer stem cells

Introduction

Pancreatic cancer is one of the most dangerous solid malignancies, characterized by its aggressiveness and metastatic potential, with a five-year overall survival rate of just 12%.^1,2 It remains as the fourth leading cause of cancer-related deaths globally, and is considered a silent disease due to the absence of early symptoms. As a result, it is often detected at a late stage, and is associated with high mortality, primarily due to lack of early biomarkers for detection and the resistance to traditional therapeutic regiments such as chemotherapy and radiotherapy.^1-3 Several biomarkers have been proposed for the early detection of pancreatic cancer, including serum carbohydrate antigen (CA19-9),^4,5 carcinoembryonic antigen (CEA),⁵ methylated DNA biomarkers (CD1D, KCNK12, CLEC11A, NDRG4, IKZF1, and PKRCB), and mutant KRAS.⁶ However, these markers still have significant limitations, including low sensitivity and specificity,⁵ difficulty in detecting tumor recurrence after surgical resection,⁷ and poor differentiation between pancreatic cancer and normal pancreatitis.⁶

The human aldehyde dehydrogenase (ALDHs) superfamily comprises 19 isoenzymes that play crucial roles in cell survival, differentiation, carcinogenesis and resistance to chemo-, radio- and targeted therapy. The ALDH isoenzymes vary in their tissue distribution, subcellular location, and preferred substrates. Importantly, ALDH isoenzymes are involved in several different biological functions and typically protect cells against aldehyde toxicity.⁸ Aldehyde dehydrogenase-1A1 (ALDH1A1), one of the main members of the ALDH1 family which includes Aldehyde dehydrogenase-1A2 (ALDH1A2) and Aldehyde dehydrogenase-1A3 (ALDH1A3), has a higher affinity for the oxidizing both all-trans and 9-cis-retinal molecule compared to ALDH1A2 and ALDH1A3.⁹ Therefore, ALDH1A1 is considered a key regulator in physiological biosynthetic processes, including the detoxification of endogenous and exogenous aldehyde substrates, by catalyzing oxidation with nicotinamide-adenine dinucleotide phosphate positive [NAD(P)⁺].¹⁰ Abnormal expression of ALDH1A1 has been implicated in a variety of diseases, including obesity,¹¹ diabetes,¹² inflammation,¹³ Alzheimer,¹⁴ and several cancers such as pancreatic cancer,^15-17 lung cancer,^18,19 gastric cancer,^20-22 hepatocellular carcinoma,²³ breast cancer,^24,25 cervical carcinoma,²⁶ head and neck squamous cell carcinoma,²⁷ papillary thyroid carcinoma,²⁸ melanoma,²⁹ prostate cancer,³⁰ and ovarian cancer.³¹ A correlation exists between ALDH1A1 expression levels and the development or progression of these diseases. Furthermore, ALDH1A1 plays a significant role in regulating chemoresistance in various cancer types including pancreatic cancer.^15,16 In particular, ALDH1A1 is one of the key clinical isozymes involved in the development of cancer stem cells.^32-34 Based on these findings, ALDH1A1 is currently considered a potential biomarker for diagnosing and detecting cancer as well as for identifying cancer stem cells. In this review, we summarized the significant functions of ALDH1A1 as the novel regulator of chemoresistance, prognosis and pancreatic cancer stem cell development.

Classification and Function of the Human Aldehyde Dehydrogenase (ALDHs) Superfamily

The ALDHs superfamily consisting of 19 genes that encode 19 isoenzymes including ALDH1A1, ALDH1A2, ALDH1A3, Aldehyde dehydrogenase-1B1 (ALDH1B1), Aldehyde dehydrogenase-1L1 (ALDH1L1), Aldehyde dehydrogenase-1L2 (ALDH1L2), Aldehyde dehydrogenase-3A1 (ALDH3A1), Aldehyde dehydrogenase-3A2 (ALDH3A2), Aldehyde dehydrogenase-3B1 (ALDH3B1), Aldehyde dehydrogenase-3B2 (ALDH3B2), Aldehyde dehydrogenase-4A1 (ALDH4A1), Aldehyde dehydrogenase-5A1 (ALDH5A1), Aldehyde dehydrogenase-6A1 (ALDH6A1), Aldehyde dehydrogenase-7A1 (ALDH7A1), Aldehyde dehydrogenase-8A1 (ALDH8A1), Aldehyde dehydrogenase-9A1 (ALDH9A1), Aldehyde dehydrogenase-16A1 (ALDH16A1) and Aldehyde dehydrogenase-18A1 (ALDH18A1). These enzymes plays a crucial role in the organism’s detoxification processes by catalyzing the NAD(P) dependent oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding carboxylic acids (Table 1).^35,36 Furthermore, ALDHs are highly significant in defense mechanisms and detoxification, as well as key biosynthetic, metabolic and signal transduction pathways related to both pathogenicity and health conditions, such as neurogenerative diseases, cancer and resistance to chemotherapy.³⁶ In particular, with the four main abnormalities of ALDHs-abnormal expression, insufficient activity, high activity and overexpression, are pivotal in cancer pathology.³⁶ Specifically: (1) Abnormal expression of ALDHs may either enhance carcinogenesis or protect cancer cell population against chemotherapy^36,37; (2) Insufficient ALDH activity can increases carcinogenesis by leading to aldehyde accumulation as reactive oxygen species (ROS) production³⁶; (3) High ALDH activity in cancer stem cells is associated with their survival and antioxidant properties^36,38; and (4) ALDH overexpression in cancer stem cell populations provides a significant survival advantage and contribute to chemoresistance.³⁶ As a result, abnormal expression of ALDHs correlates with poor clinical outcome, and ALDHs are considered potential biomarkers of various types of cancers. For example: ALDH1A1, ALDH3A1 and ALDH3A2 are potential markers in blood cancer^39,40; ALDH1A1 and ALDH1A3 in breast cancer^41,42; ALDH1A3, ALDH3A1 and ALDH7A1 in oral cancer^43,44; ALDH1A1, ALDH1A3 and ALDH1B1 in colorectal cancer^45-48; ALDH1A1, ALDH1A3, ALDH7A1 and ALDH1L2 in pancreatic cancer^49,50; ALDH1A1, ALDH3A1, ALDH1L2, ALDH3B1, ALDH7A1, ALDH18A1 and ALDH1L1 in lung cancer^51-54; ALDH1A1, ALDH1A3, ALDH3A1 and ALDH18A1 in melanoma cancer^34,55,56; ALDH1A1, ALDH7A1, ALDH4A1, ALDH9A1 and ALDH18A1 in prostate cancer^30,57,58; ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A2, ALDH7A1, ALDH3B1 and ALDH5A1 in ovarian cancer^31,59,60; ALDH1A1 and ALDH1A3 in head and neck squamous cell carcinoma^61,62; ALDH1A1, ALDH1A3, ALDH1B1, ALDH1L1, ALDH6A1, ALDH18A1, ALDH3B1 and ALDH3B2 in liver cancer^63,64; and ALDH1A1, ALDH1A3 and ALDH1L1 in brain tumors.^65,66

Table 1.

Classification of the Human Aldehyde Dehydrogenase (ALDH) Superfamily.

Given Name	Actual Name	Chromosomal Location
ALDH1A1	Aldehyde dehydrogenase-1A1	9q21.13
ALDH1A2	Aldehyde dehydrogenase-1A2	15q21.3
ALDH1A3	Aldehyde dehydrogenase-1A3	15q26.3
ALDH1B1	Aldehyde dehydrogenase-1B1	9p13.1
ALDH1L1	Aldehyde dehydrogenase-1L1	3q21.3
ALDH1L2	Aldehyde dehydrogenase-1L2	12q23.3
ALDH3A1	Aldehyde dehydrogenase-3A1	17p11.2
ALDH3A2	Aldehyde dehydrogenase-3A2	17p11.2
ALDH3B1	Aldehyde dehydrogenase-3B1	11q13.2
ALDH3B2	Aldehyde dehydrogenase-3B2	11q13.2
ALDH4A1	Aldehyde dehydrogenase-4A1	1p36.13
ALDH5A1	Aldehyde dehydrogenase-5A1	6p22.3
ALDH6A1	Aldehyde dehydrogenase-6A1	14q24.3
ALDH7A1	Aldehyde dehydrogenase-7A1	5q23.3
ALDH8A1	Aldehyde dehydrogenase-8A1	6q23.3
ALDH9A1	Aldehyde dehydrogenase-9A1	1q24.1
ALDH16A1	Aldehyde dehydrogenase-16A1	19q13.33
ALDH18A1	Aldehyde dehydrogenase-18A1	10q24.1

Aldehyde Dehydrogenase-1A1 (ALDH1A1) and Chemoresistance

ALDH1A1 is also considered a highly conserved homo-tetramer (∼55 kDa monomer), with the retina being its preferred location.⁶⁷ The important role of ALDH1A1 involves the formation of transcriptional regulators essential for normal cell growth and differentiation. Additionally, ALDH1A1 is involved in the oxidation of retinaldehyde to retinoic acid.⁶⁸ One of the prominent cytotoxic roles of the ALDH isozyme superfamily is to protect the body against various harmful aldehydes, both endogenous and exogenous.^69,70 Endogenous aldehydes are produced during the metabolism of amino acids, alcohols, lipids and vitamins, whereas exogenous aldehydes, as intermediates or products, are derived from the metabolism of a various environmental agents and cytotoxic drugs.⁷¹ Furthermore, oxidative stress can damages DNA and proteins, triggering lipid peroxidation of cellular phospholipids, which produce more than 200 reactive aldehyde species. By metabolizing these aldehydes, ALDHs help reduce oxidative stress and downregulation of ALDHs’ activity has been shown to accumulate reactive oxygen species in cancer stem cells, leading to DNA damage and apoptosis.⁷²

Highly elevated levels of ALDH enzymes in several cancer cell lines as well as in patients, lead to the development of resistance to both chemotherapy and radiation.⁷³ In particular, ALDH1A1 is not only involved in cell differentiation and resistance to chemotherapy and radiotherapy but also in malignant progression in cancer patients.⁷⁴ Abnormal expression of ALDH1A1 has been reported to cause chemoresistance to the following drugs: doxorubicin, paclitaxel, cyclophosphamide and tamoxifen in breast cancer^24,73,75,76; paclitaxel and cisplatin in lung cancer^77,78; cisplatin in cervix cancer⁷⁹; 5-fluorouracil in esophageal squamous cell carcinoma⁸⁰; platinum-based therapy in ovarian cancer⁸¹; cyclophosphamide in chronic myelogenous leukemia⁸²; and gemcitabine and 5-fluorouracil in pancreatic cancer.^15-17,83 Duong et al investigated the significant correlation between the level of endogenous ALDH1A1 and both intrinsic and acquired resistance to gemcitabine in MIA PaCa-2 pancreatic cancer cells. The expression level of ALDH1A1 was high in MIA PaCa-2 cells and significantly higher in the gemcitabine-resistant MIA PaCa-2 cells; Interestingly, ALDH1A1 knockdown significantly reduced ALDH1A1 expression, inhibited cell proliferation, and, when combined with gemcitabine, significantly decreased cell survival, increased apoptotic cell death and enhanced the accumulation of cells at the S-phase. This effect was observed not only in parental MIA PaCa-2 cells but also in the gemcitabine-resistant MIA PaCa-2 cells.¹⁵ Moreover, the combination of dasatinib and gemcitabine may overcome gemcitabine resistance by decreasing ALDH1A1 expression.¹⁶ Additionally, NRF2 could promote ALDH1A1 expression, and silencing NRF2 might enhance the anti-proliferative activity of 5-fluorouracil in pancreatic cancer.¹⁷ Furthermore, cross-resistance to 5-fluorouracil, oxaliplatin, cisplatin and irinotecan acquired through long-term treatments with increasing 5-fluorouracil levels in HT-29 colorectal cancer cells, is associated with the conversion of ALDH1A1 to ALDH1A3 isoform.⁸⁴ Small interfering RNA (siRNA) inhibition of ALDH1A1 isoforms sensitized HT-29 cells to capecitabine and 5-fluorouracil.⁴⁶ Regulation of ALDH1A1 expression using siRNA increased the sensitivity of lung cancer cells to cyclophosphamide.⁸⁵ Therefore, ALDH1A1 knockdown increases chemoresistance and may reverses chemoresistance in breast cancer,⁸⁶ lung adenocarcinoma,⁸⁷ cervical cancer,²⁶ ovarian cancer,^81,88 pancreatic cancer,¹⁵ esophageal squamous cell carcinoma,⁸⁰ and chronic myelogenous leukemia.⁸²

Furthermore, several scientific research projects have been published providing additional evidence of the chemical resistance associated with ALDH1A1 in various cancer types. High expression of SOX9 correlates with poor survival in non-small cell lung cancer patients. SOX9 is induced by cisplatin exposure in human lung cancer cells, where ALDH1A1, a direct transcriptional target of SOX9, promotes chemotherapy response in non-small cell lung cancer cells.⁸⁹ ALDH1A1-positive cell populations have been shown to be associated with chemoresistance in patients with ovarian cancer, and stable knockdown of ALDH1A1 significantly reduced the formation of colonies of ovarian cancer cells.⁹⁰ ALDH overexpression has also been linked to several properties of ovarian cancer-like cells, such as increased invasiveness, colony formation and chemoresistance.⁹¹ ALDH1A1 plays an important role in maintaining ovarian cancer stem cell-like properties and may mediate carboplatin resistance, through altered regulation of cell cycle and repair networks DNA.⁹² In pancreatic cancer, specific inhibition of ALDH1A1 using A37 (an ALDH1A1 inhibitor) or ALDH1A1 siRNA/shRNA reduced cell proliferation, metabolism and colony formation, thereby significantly sensitizing pancreatic cells to treatment with gemcitabine, radiation or chemoradiation in MIA PaCa-2 and Panc 05.04 cells.^15,83 These finding highlight the crucial role of ALDH1A1 in pancreatic cancer biology, particularly in therapy resistance.

Aldehyde Dehydrogenase-1A1 (ALDH1A1) and Prognosis of Cancer

ALDH1A1, one of three phenotypes of ALDH1, is markers of both normal tissue stem cells and cancer stem cells and are involved in self-renewal, differentiation, and proliferation. However, overexpression of ALDH1A1 in malignant tumors and cancer stem cells, is strongly associated with poor prognosis, tumor aggressiveness and drug resistance.^9,32,41 In breast cancer, high expression of ALDH1A1 was significantly correlated with poorer overall survival and worse.^93,94 In lung cancer, increased ALDH1A1 expression is associated with survival in patients with non-small cell lung cancer, and higher ALDH1A1 expression was positively correlated with late disease stage (stage III and IV) and poor survival.^95,96 In cervical cancer, high expression of ALDH1A1 is significantly associated with poor prognosis.²⁶ In esophageal squamous cell carcinoma, higher ALDH1A1 expression is significantly correlated with the stages, invasion depth and lymph node metastasis.⁹⁷ In ovarian cancer, increased expression of ALDH1A1 is significantly associated with more favorable disease-free and overall survival.⁹² In liver cancer, a high percentage of ALDH1A1 upregulation in primary liver cancer specimens is significantly associated with well-differentiated pathology and favorable clinical prognosis.⁹⁸ In gastric cancer, high expression of ALDH1A1 is significantly associated with invasion depth, lymph node metastasis and stage of disease.^20,99 In glioma, overexpression of ALDH1A1 is significantly associated with invasion, progression and poor prognosis.⁶⁶ In oral squamous cell carcinoma, high expression of ALDH1A1 is significantly associated with invasiveness and poor prognosis.¹⁰⁰ In pancreatic cancer, increased expression of ALDH1A1 is associated with poor prognosis and ALDH1A1 plays an important role in the development of metastatic disease, negatively affecting the overall survival.¹⁰¹ However, low expression of ALDH1A1 has emerged as an independent adverse prognostic marker, associated with shortened disease free and overall survival in patients with pancreatic cancer.¹⁰² Furthermore, low expression of ALDH1A1 is demonstrated as an independent prognostic marker for a poor clinical outcome in pancreatic cancer.¹⁰² The inconsistences of ALDH1A1 expression across various cancer types depend on clinical characterization, genetic landscape and molecular mechanism specific to each cancer type. As each type of cancer has its own distinct clinical profile, genetic and molecular characteristics, the correlation between ALDH1A1 expression, progression and prognosis may vary. However, a larger study with more patients are needed for further standardized prospective research to determine the significant role of ALDH1A1 as a prognostic and predictive marker for tumor progression and response to chemotherapy, such as gemcitabine in pancreatic cancer. In conclusion, the abnormal expression of ALDH1A1 can be an important factor in cancer progression, poor survival, poor prognosis and metastasis in these patients.

Aldehyde Dehydrogenase-1A1 (ALDH1A1) and Cancer Stem Cells

Cancer stem cells are defined as a small population of cancer cells with high self-renewal, differentiation and tumor-initiating functions.¹⁰³ Additionally, cancer stem cells are resistant to chemotherapy and radiotherapy, and are therefore responsible for post-treatment tumor recurrence as well as invasion and metastasis.^104,105 ALDH1A1, an important regulator of cancer stem cells, plays a significant role in retinoid metabolism and the removal of toxic aldehydes and reactive oxygen species from cancer stem cells, thereby influencing their essential properties, such as stemness, cell differentiation and tumor resistance.⁹ ALDH1A1 has also been demonstrated as a therapeutic regulator of various cancer stem cells including breast cancer,^41,93,106 lung cancer,⁹⁶ esophagus cancer,⁹⁷ colorectal cancer,¹⁰⁷ liver cancer,¹⁰⁸ ovarian cancer,¹⁰⁹ and pancreatic cancer.¹⁰¹ ALDH1A1, an important marker of cancer stem cells, helps maintain the characteristics of these cells, modifies metabolism and promotes DNA repair. Furthermore, ALDH1A1 is highly expressed in cancer stem cells but not in normal tissues.⁹ In esophageal squamous cell carcinoma, ALDH1A1 maintains the cancer stem-like cells properties by activating the AKT signaling pathway and interacting with β-catenin⁸⁰; In breast cancer, ALDH1A1 promote tumor angiogenesis via retinoic acid/HIF-1α/VEGE signaling in MCF-7 breast cancer.¹¹⁰ ALDH1A1 activity in tumor-initiating cells remodels myeloid-derived suppressor cells to promote breast cancer pregression¹⁰⁶; In ovarian cancer, co-expression of Spalt-like transcription factor 4 (SALL4) and ALDH1A1 is associated with tumor aggressiveness and poor survival in patients with serous ovarian carcinoma¹¹¹ and ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator, but it may be potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitor¹¹²; In bladder cancer, YAP regulates ALDH1A1 expression and stem cell property of bladder cancer cells¹¹³; Specifically, Dickkopf-1 (DKK1) maintains cancer stem-like properties of esophageal carcinoma cells via ALDH1A1/SOX2 axis.¹¹⁴ Therefore, ALDH1A1 can serve as diagnosis and therapeutic target for cancer stem cells, proving new insight and strategies for reliable tumor treatments.

Aldehyde Dehydrogenase-1A1 (ALDH1A1) and Therapeutic Target Drugs

Given the important role of ALDH1A1 in several types of cancer, it can be a pivotal target for cancer treatment, either in monotherapy or in combination with chemotherapy in ovarian cancer,^115-117 breast cancer,^106,118-120 prostate cancer,¹²¹ and non-small lung cancer.¹²² In ovarian cancer, A37/CM37, a novel small molecule inhibitor of ALDH1A1, and NCT-501, an selective inhibitor of ALDH1A1, sensitize ovarian cancer cell to cisplatin,¹¹⁶ and Olaparib,¹¹⁷ respectively. In breast cancer, BDC, a synthetic curcumin analog targeting ALDH1A1, could overcome drug resistance.¹¹⁸ Disulfiram, an ALDH1A1 inhibitor, in combination with gemcitabine, significantly inhibited breast tumor growth and tumorigenesis.¹⁰⁶ On the other hand, Ellipticine inhibited mammosphere formation in ALDH1A1-overexpressing breast cancer stem cells.¹¹⁹ Quercetin inhibits the proliferation, clonal expansion and mammosphere formation of CD44+/CD24- breast cancer stem cells by targeting ALDH1A1 and other pathways.¹²⁰ In prostate cancer, Silybin significantly inhibited the proliferation, invasion and metastasis of prostate cancer cells by reducing ALDH1A1 expression levels.¹²¹ In non-small cell lung cancer, β-escin inhibited tobacco carcinogen-induced lung tumor formation by modulating ALDH1A1 positive cells.¹²² Particularly, treatment of pancreatic cancer cells with Disulfiram resulted in reduction in ALDH1A1-high expressing cells. Therefore, Disulfiram can be a promising therapy for effective treatment ALDH1A1-high expressing pancreatic cancer.

Conclusion and Future Perspectives

ALDH1A1, one of three key ALDH1 isoenzymes, is considered a novel regulator of chemoresistance, prognosis and cancer stem cells in various types of cancer, including pancreatic cancer. In the present review, we briefly summarize how the abnormal expression of ALDH1A1 is significantly associated with chemoresistance, cancer prognosis and cancer stem cells in malignant tumors.

Preclinical and clinical studies designed to evaluate different therapeutic strategies could improve the ability to treat cancer patients by inhibiting ALDH1A1 in combination with chemotherapy. Additionally, ALDH1A1 could be utilized as a clinical regulator to control chemoresistance, prognosis and cancer stem cells including pancreatic cancer (Figure 1). Overall, significant future advances in these areas of precision medicine targeting ALDH1A1 could be clinically meaningful and enhance the treatment efficacy for several patient populations, including those with pancreatic cancer.

Figure 1.

The clinical role of Aldehyde dehydrogenase-1A1 (ALDH1A1) in pancreatic cancer. ALDH1A1 regulates several hallmarks of cancer as a clinical regulator to control chemoresistance, prognosis and cancer stem cells. In pancreatic, RA binds RAR to drive ALDH1A1 to induce higher expression of ALDH1A1 which is responsible for significant activation of the AKT/GSK3β signaling pathway in regulation of chemoresistance, prognosis and cancer stem cells. ALDH1A1: Aldehyde dehydrogenase-1A1; RA: Retinoic acid; RAR: Retinoic acid receptor; ROS: Reactive oxygen species; AKT: Protein kinase B; GSK3β: Glycogen synthase kinase-3 beta.

Footnotes

Author Contributions

HQD, MCH and THD conceived the concept and wrote the manuscript. THN, PTN, VTL, TND, VLN critically revised the manuscript for intellectual content. HQD organized and revised the final version of the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the National Foundation for Science and Technology Development (NAFOSTED; grant no. 108.06-2020.03) (H.Q.D).

Ethical Statement

ORCID iD

Hong-Quan Duong

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