1. Introduction

Aldehyde dehydrogenases (ALDHs) are evolutionarily conserved proteins that are involved in the regulation of diverse metabolic processes including proliferation and differentiation, via detoxifying aldehydes to protect cells in both eukaryotes and prokaryotes [1]. In eukaryotic cells, there are 19 ALDH members distributed in several subfamilies [2]. The ALDH1 subfamily members that can oxidize larger substrates as retinol (vitamin A) generate the signaling molecule retinoic acid, which activates its nuclear receptors to regulate gene expression ^[3][4][3,4]. The subfamily member ALDH1A1 (https://www.omim.org/entry/100640) has the capacity to detoxify lipid peroxidation byproducts acrolein, 4-hydroxy-2-nonenal (4-HNE), and malondialdehyde, while it is substantially more resistant to inactivation than the mitochondrial enzyme ALDH2 [5]. 4-HNE causes a decrease in the activity of DNA double-strand break repair proteins, thereby exacerbating DNA damage under oxidative conditions in cells [6]. This means that under conditions of increased oxidant stress ALDH1A1 would be a key enzyme for recovery of the activity of both other aldehyde dehydrogenases, as well as other detoxifying enzymes. ALDH1A1 would allow the additional recovery of other cellular protective mechanisms, including DNA repair that are inactivated by byproducts of lipid peroxidation ^[7][8][7,8]. ALDH activity is crucial for stem cell function in the hematopoietic system, and high ALDH1A1 activity has a role in both protecting hematopoietic stem cells (HSC) from various toxic molecules and also for promoting HSC differentiation, with a partial overlap by ALDH3A1 [9]. Hematopoietic cells from ALDH1A1-deficient mice exhibited increased sensitivity to cyclophosphamide in a non-cell-autonomous manner, consistent with its role in cyclophosphamide metabolism in the liver. However, ALDH1A1 deficiency did not affect hematopoiesis, HSC function, or the capacity to reconstitute irradiated recipients in young or old adult mice [10]. The involvement of ALDH1A1 in HSC differentiation can be attributed to the generation of retinoic acid, as retinoic acid can reverse the block of HSC differentiation by ALDH1A1 inhibition [11]. The partial protective role of ALDH1A1 in HSC biology suggests that it may have a similar role in acute myeloid leukemia (AML) which is a bone marrow malignancy of the myeloid line of blood cells; an abnormal clone that develops from either a myeloid progenitor cell or a myeloblast can give rise to AML, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Indeed, a positive correlation has been shown between low/absent ALDH1A1 activity and favorable prognosis in AML, as expected: patients with AML cells lacking ALDH1A1 had a favorable prognosis, and ALDH1A1⁻ cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide [12]. ALDH1A1 activity appears indispensable for the survival of AML cells, in contrast to normal HSC [13]. Consequently, targeting ALDH1A1 will probably be an important cornerstone in overcoming therapy resistance in AML.

In general, for cancer stem cells ALDH1A1 was proposed as a reporter & marker for self-renewal (clonogenicity), chemoresistance, invasiveness, and metastasis ^[14][15][25,26]. Oxazaphosphorine drugs (such as cyclophosphamide, ifosfamide, and trofosfamide) are broad-spectrum alkylating agents that generate toxic aldehydes; ALDH1A1 contributes significantly to the detoxification of the latter ^[16][27]. ALDH1A1 has been proposed to facilitate cancer via the maintenance of cancer stem cell properties, modification of metabolism, and promotion of DNA repair, emphasizing however that ALDH1A1 is not uniformly associated with cancer progression, with several cancer types having a favorable prognosis with higher ALDH1A1 expression ^[17][28]. This suggests that the role of ALDH1A1 can become redundant for cancer cells under certain conditions, while it can support essential physiological functions and thereby benefit the host organism.

In non-small cell lung cancer, which is the most common type of neoplasia worldwide, ALDH1A1 is highly expressed after the loss of the aryl hydrocarbon receptor block on carcinogenesis by constitutively active KRAS ^[18][29]. In the model for the study of pancreatic intraepithelial neoplasia progression to cancer, deficiency of the regulator ARID1A (AT-rich interaction domain 1A) triggers the expression of ALDH1A1, which enables KRAS-driven carcinogenesis by attenuating cellular senescence (KRAS stands for Kirsten oncogene of rat sarcoma, based on its original discovery) ^[19][30]. Hypoxia enables NFκB-driven epithelial–mesenchymal transition, induction of colony and spheroid formation, and ALDH1 activity for pancreatic cancer cells (NFκB stands for nuclear factor κB) ^[20][31].

In the malignant subtype of human intrahepatic cholangiocarcinoma, the loss of ARID1A was an independent prognostic factor for the overall survival of patients (p = 0.023); ARID1A and histone deacetylase 1 (HDAC1) were directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A1 expression. ARID1A knockout cells exhibited significantly enhanced migration, invasion, and sphere formation activity and ALDH1A1 expression ^[21][32].

In prostate cancer, inflammatory cues activate I kappa B kinase beta (IKKβ) to phosphorylate ARID1A, leading to its degradation via E3 ubiquitin ligase β-TRCP; ARID1A downregulation, in turn, silences the enhancer of A20 deubiquitinase, a critical negative regulator of NFκB signaling, and thereby unleashes C-X-C motif chemokine receptor 2 (CXCR2) ligand-mediated myeloid-derived suppressor cell chemotaxis that permits cancer progression ^[22][33]. In prostate adenocarcinoma, ALDH1A1 shows a statistically significant association with tumor stage (p < 0.001), extraprostatic extension (p < 0.001), and lymphovascular invasion (p = 0.001) ^[23][34]. Patterns of mutual exclusivity for ALDH1A1 and ALDH1A3 expression may indicate a certain degree of redundancy between ALDHs in prostate cancer ^[24][35]. It is also worth noting that in contrast to cancer cells, stromal cells may lose ALDH1A1 during cancer progression ^[25][36].

In ovarian cancer samples obtained from patients’ ascites, ALDH activity directly correlated to platinum resistance. In the same study in cultured cells, ALDH1A1 knockdown suppressed carboplatin-induced Poly-(ADP-ribose) polymerase (PARP) activity and expression of replication fork associated Fanconi anemia pathway proteins FANCD2 and FANCJ, excision repair protein XRCC1 (X-ray repair cross-complementing 1), replication checkpoint kinase protein 1; while increasing expression of BRCA1 substantially ^[26][37]. Ovarian cancer cell lines treated with an ALDH1A1 inhibitor had increased oxidant stress and markers of DNA damage, with diminishing spheroid formation ^[27][38].

Cultured breast cancer cells MDA-2J2 that are resistant to paclitaxel, doxorubicin, staurosporine, and multikinase inhibitor sorafenib, could be sensitized by ALDH1A1 gene silencing, demonstrating the capacity of ALDH1A1 to mediate resistance to a variety of antineoplastic pharmaceutical agents ^[28][39].

Human sarcoma cell line subclones, xenografts, and patient specimens that were selected for resistance to sorafenib had cancer stem cell properties, increased aldehyde dehydrogenase activity, and staining for ALDH1A1 ^[29][40]. Sorafenib, a tyrosine kinase inhibitor, is used to treat FMS-related tyrosine kinase-3 internal tandem duplication (FLT3ITD) -positive AML ^[30][31][41,42].

In colorectal cancer stem cells, mutant P53 bound the promoter sequence of the ALDH1A1 gene, and activated its expression; ALDH1A1 expression was essential to the mutant P53-dependent chemotherapy resistance ^[32][43]. Loss of wildtype P53 in cultured cells enriched for cancer stem cell properties including aldehyde dehydrogenase activity and drug efflux, which were reversed by the reintroduction of wildtype P53 ^[33][44].

In melanoma cells ALDH1A1, through the retinoic acid pathway, regulated the activation of NFκB and expression of C-X-C Motif Chemokine CXCL8; in co-cultures of melanoma with endothelial cells, the addition of a CXCL8 neutralizing antibody to endothelial cells dampened endothelial angiogenic features, both at the molecular level in terms of gene and protein expression of mediators of the Notch pathway, and at the functional level in terms of proliferation, scratch assay, tube formation and permeability ^[34][45].

ARID1A is normally also repressed by microRNA223 (mir223), which is transiently activated by NFκB during the late stages of inflammation as a negative feedback gene that terminates inflammation ^[35][36][46,47]. In AML mir223 is essential for leukemia-initiating cells, and at the same time for recovery of the organism from leukemia, for a favorable outcome ^[37][48]. Apparently, mir223 becomes redundant once permitting ALDH1A1 promoter acetylation. Alternatively, ARID1A can be degraded by the proteasome in cells ^[38][49]. This could also permit sustained ALDH1A1 gene expression: AML cells possess significant proteasome activity, which coincides with aggressive disease, and is the main mechanism of NFκB activation because it degrades the inhibitor IκB ^{[39][40][41][42]}[50,51,52,53]. In AML, complete remission appears to associate with a rebound in ARID1A expression ^[43][54]. Also on the same note, mutations in ARID1A are associated with a negative AML course, and in mouse model AML progression ^[44][45][55,56].

In diffuse large B cell lymphoma ARID1A mutations do occur ^[46][57], which might facilitate ALDH1A1 expression. Actually, in diffuse large B cell lymphoma, ALDH1A1 enhances phosphorylation of transcription factors STAT3 (signal transducer and activator of transcription 3) and NFκB, augmenting clonogenicity, suppressing caspase activity, and inducing resistance to the chemotherapeutic mixture consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone ^[47][58]. ALDH activity alone suffices to select cells that initiate tumors in mice ^[48][59].