Abstract

Aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes often upregulated in cancer cells and associated with therapeutic resistance. In humans, the ALDH family comprises 19 isoenzymes active in the majority of mammalian tissues. Each ALDH isoform has a specific differential expression pattern and most of them have individual functional roles in cancer. ALDHs are overexpressed in subpopulations of cancer cells with stem-like features, where they are involved in several processes including cellular proliferation, differentiation, detoxification and survival, participating in lipids and amino acid metabolism and retinoic acid synthesis. In particular, ALDH enzymes protect cancer cells by metabolizing toxic aldehydes in less reactive and more soluble carboxylic acids. High metabolic activity as well as conventional anticancer therapies contribute to aldehyde accumulation, leading to DNA double strand breaks (DSB) through the generation of reactive oxygen species (ROS) and lipid peroxidation. ALDH overexpression is crucial not only for the survival of cancer stem cells but can also affect immune cells of the tumour microenvironment (TME). The reduction of ROS amount and the increase in retinoic acid signaling impairs immunogenic cell death (ICD) inducing the activation and stability of immunosuppressive regulatory T cells (Tregs). Dissecting the role of ALDH specific isoforms in the TME can open new scenarios in the cancer treatment. In this review, we summarize the current knowledge about the role of ALDH isoforms in solid tumors, in particular in association with therapy-resistance.

Highlights

  • Aldehyde dehydrogenases are a family of NADP+-dependent enzymes that participate in several physiological and biosynthetic processes, catalyzing the oxidation of toxic aldehydes into carboxylic acids and participating in the synthesis of molecules involved in cell differentiation, proliferation and survival as retinoic acid (RA), γ-aminobutyric acid, and betaine [1]

  • We summarize the current state of art on the role of aldehyde dehydrogenases (ALDHs) isoenzymes in solid tumors, with a particular focus on their involvement in cancer stem cells (CSCs), therapy resistance and immune suppression

  • Aldehyde dehydrogenases isoforms are often overexpressed by cancer cells, and, in particular, are responsible for the maintenance of the stem-cell-like phenotype, leading to cancer progression, chemo- and radio-therapy resistance, and immune

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Summary

Frontiers in Medicine

Citation: Zanoni M, Bravaccini S, Fabbri F and Arienti C (2022) Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance. Aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes often upregulated in cancer cells and associated with therapeutic resistance. In humans, the ALDH family comprises 19 isoenzymes active in the majority of mammalian tissues. Each ALDH isoform has a specific differential expression pattern and most of them have individual functional roles in cancer. ALDHs are overexpressed in subpopulations of cancer cells with stem-like features, where they are involved in several processes including cellular proliferation, differentiation, detoxification and survival, participating in lipids and amino acid metabolism and retinoic acid synthesis. In particular, ALDH enzymes protect cancer cells by metabolizing toxic aldehydes in less reactive and more soluble carboxylic acids. High metabolic activity as well as conventional anticancer therapies contribute to aldehyde accumulation, leading to DNA double strand breaks (DSB) through the generation of reactive oxygen species (ROS) and lipid peroxidation. ALDH overexpression is crucial not only for the survival of cancer stem cells but can also affect immune cells of the tumour microenvironment (TME). The reduction of ROS amount and the increase in retinoic acid signaling impairs immunogenic cell death (ICD) inducing the activation and stability of immunosuppressive regulatory T cells (Tregs). Dissecting the role of ALDH specific isoforms in the TME can open new scenarios in the cancer treatment. In this review, we summarize the current knowledge about the role of ALDH isoforms in solid tumors, in particular in association with therapy-resistance. Keywords: aldehyde dehydrogenase, cancer stem cell, double strand brakes (DSB), therapeutic resistance, immunosuppression Abbreviations: ALDHs, aldehyde dehydrogenases; DSB, DNA double strand breaks; ROS, reactive oxygen species; TME, tumor microenvironment; ICD, immunogenic cell death; Tregs, regulatory T cells; RA, retinoic acid; RARα, retinoic acid receptor α; RXR, retinoic X receptor; ERα, estrogen receptor α; SCs, normal stem cells; CSCs, cancer stem cells; NER, nucleotide excision repair; BER, base excision repair; HR, homologous recombination; 4-HNE, 4-hydroxy-2-non-enal; MDA, acetaldehyde malondialdehyde; 4-HHE, 4-hydroxy-2-hexenal; LPO, lipid peroxidation; PARP1, poly (ADP-ribose) polymerase 1; EGFR, epidermal growth factor receptor; MMEJ; microhomology-mediated end joining; ER, endoplasmatic reticulum; DEAB, N,N-diethylaminobenzaldehyde; HNSCC, head and neck squamous cell carcinoma; DETC, S-methylN,N-diethyldithiocarbamate; Me-DDTC, S-methyl-N,N-diethyldithiocarbamate; TGF-β: transforming growth factor β; DCs: dendritic cells; GM-CSF: granulocyte–macrophage colony-stimulating factor; PPARγ: peroxisome proliferator-activated receptor γ; DIMATE: 4-dimethylamino-4-methyl-pent-2-ynthioic acid-Smethylester.

INTRODUCTION
FUNCTION OF ALDEHYDE DEHYDROGENASES
ALDEHYDE DEHYDROGENASES IN NORMAL AND CANCER STEM CELLS
Oxidation of retinaldehyde to retinoic acid
In all cancers
ALDEHYDE DEHYDROGENASES IN RESPONSE AND RESISTANCE TO THERAPIES
TARGETING ALDEHYDE DEHYDROGENASES IN CANCER
CONCLUSIONS AND FUTURE PERSPECTIVES

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