International Journal of Molecular Sciences

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Dear Colleagues,

Aldehyde dehydrogenase (ALDH) plays important roles in multiple biological processes, such as the oxidation of biogenic and xenogenic aldehydes to carboxylic acids (including the detoxification of alcohol-derived acetaldehyde), the formation of retinoic acid, oxidative stress responses, and cell differentiation. In humans, the ALDH family comprises 19 isoenzymes which are localized in the cytoplasm, mitochondria, nucleus, and endoplasmic reticulum, active in the majority of mammalian tissues. Mutations and polymorphisms in ALDH genes lead to losses of function that are involved in a variety of diseases, such as cardiovascular diseases, diabetes, obesity, neurodegenerative diseases, stroke, and also malignant diseases. The high expression of ALDHs found in various neoplastic tissues suggests that these enzymes play a key role in the progression, differentiation, and survival of cancer cells.

In this Special Issue, we welcome original research and literature reviews discussing various aspects of ALDHs in relation to tumorigenesis to summarize and enlarge our understanding of the meaning of ALDHs in cancer diseases.

Dr. Karolina Orywal
Dr. Beata Želazowska-Rutkowska
Guest Editors

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Keywords

aldehyde dehydrogenase
molecular regulation
molecular tumor pathology
gene polymorphism
gene expression
polymorphism
ALDH isoenzymes
ALDH inhibitors
therapeutic targets
prognosis
cancer stem cell
stem cell marker
biomarker
retinoic acid
oxidative stress
toxic aldehydes
tumor microenvironment
angiogenesis
metastasis

Published Papers (2 papers)

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Research

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18 pages, 4838 KiB

Open AccessArticle

Identifying the Molecular Drivers of Pathogenic Aldehyde Dehydrogenase Missense Mutations in Cancer and Non-Cancer Diseases

by Dana Jessen-Howard, Qisheng Pan and David B. Ascher

Int. J. Mol. Sci. 2023, 24(12), 10157; https://doi.org/10.3390/ijms241210157 - 15 Jun 2023

Cited by 1 | Viewed by 1834

Abstract

Human aldehyde dehydrogenases (ALDHs) comprising 19 isoenzymes play a vital role on both endogenous and exogenous aldehyde metabolism. This NAD(P)-dependent catalytic process relies on the intact structural and functional activity of the cofactor binding, substrate interaction, and the oligomerization of ALDHs. Disruptions on the activity of ALDHs, however, could result in the accumulation of cytotoxic aldehydes, which have been linked with a wide range of diseases, including both cancers as well as neurological and developmental disorders. In our previous works, we have successfully characterised the structure–function relationships of the missense variants of other proteins. We, therefore, applied a similar analysis pipeline to identify potential molecular drivers of pathogenic ALDH missense mutations. Variants data were first carefully curated and labelled as cancer-risk, non-cancer diseases, and benign. We then leveraged various computational biophysical methods to describe the changes caused by missense mutations, informing a bias of detrimental mutations with destabilising effects. Cooperating with these insights, several machine learning approaches were further utilised to investigate the combination of features, revealing the necessity of the conservation of ALDHs. Our work aims to provide important biological perspectives on pathogenic consequences of missense mutations of ALDHs, which could be invaluable resources in the development of cancer treatment. Full article

(This article belongs to the Special Issue Aldehyde Dehydrogenase in Cancer)

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Review

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19 pages, 864 KiB

Open AccessReview

The Molecular Context of Oxidant Stress Response in Cancer Establishes ALDH1A1 as a Critical Target: What This Means for Acute Myeloid Leukemia

by Garrett M. Dancik, Lokman Varisli and Spiros A. Vlahopoulos

Int. J. Mol. Sci. 2023, 24(11), 9372; https://doi.org/10.3390/ijms24119372 - 27 May 2023

Cited by 4 | Viewed by 1958

Abstract

The protein family of aldehyde dehydrogenases (ALDH) encompasses nineteen members. The ALDH1 subfamily consists of enzymes with similar activity, having the capacity to neutralize lipid peroxidation products and to generate retinoic acid; however, only ALDH1A1 emerges as a significant risk factor in acute myeloid leukemia. Not only is the gene ALDH1A1 on average significantly overexpressed in the poor prognosis group at the RNA level, but its protein product, ALDH1A1 protects acute myeloid leukemia cells from lipid peroxidation byproducts. This capacity to protect cells can be ascribed to the stability of the enzyme under conditions of oxidant stress. The capacity to protect cells is evident both in vitro, as well as in mouse xenografts of those cells, shielding cells effectively from a number of potent antineoplastic agents. However, the role of ALDH1A1 in acute myeloid leukemia has been unclear in the past due to evidence that normal cells often have higher aldehyde dehydrogenase activity than leukemic cells. This being true, ALDH1A1 RNA expression is significantly associated with poor prognosis. It is hence imperative that ALDH1A1 is methodically targeted, particularly for the acute myeloid leukemia patients of the poor prognosis risk group that overexpress ALDH1A1 RNA. Full article

(This article belongs to the Special Issue Aldehyde Dehydrogenase in Cancer)

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