Acetaldehyde and Retinaldehyde-Metabolizing Enzymes in Colon and Pancreatic Cancers

Abstract

Colorectal (CRC) and pancreatic cancers are two very significant contributors to cancer-related deaths. Chronic alcohol consumption is an important risk factor for these cancers. Ethanol is oxidized primarily by alcohol dehydrogenases to acetaldehyde, an agent capable of initiating tumors by forming adducts with proteins and DNA. Acetaldehyde is metabolized by ALDH2, ALDH1B1 and ALDH1A1 to acetate. Retinoic acid (RA) is required for cellular differentiation and is known to arrest tumor development. RA is synthesized from retinaldehyde by the retinaldehyde dehydrogenases, specifically ALDH1A1, ALDH1A2, ALDH1A3 and ALDH8A1. By eliminating acetaldehyde and generating RA, ALDHs can play a crucial regulatory role in the initiation and progression of cancers. ALDH1 catalytic activity has been used as a biomarker to identify and isolate normal and cancer stem cells; its presence in a tumor is associated with poor prognosis in colon and pancreatic cancer. In summary, these ALDHs are not only biomarkers for CRC and pancreatic cancer but also play important mechanistic role in cancer initiation, progression and eventual prognosis.

Gut microbiome of Moroccan colorectal cancer patients

“…It is well known that acetaldehyde is highly toxic and is recognized as a carcinogenic molecule to humans [117]. Moreover, acetaldehyde is considered a CRC biomarker and plays a crucial role in cancer initiation and progression [118]. Finally, relative abundance of genes of the pentose phosphate pathway was significantly higher in CRC samples.…”

Keap1–Nrf2 signalling in pancreatic cancer

“…ABCC1, ABCC3 and ABCC5 genes) are under Nrf2/ARE-mediated regulation, and increased expression of these transporters in PDAC is associated with a poor treatment response (Mohelnikova-Duchonova et al, 2013). The basal and inducible expression of several phase I and phase II drug detoxification enzymes by the Nrf2/ARE system is widely recognised, and over expression of aldo-keto reductase Li et al, 2013;Zhang et al, 2014;Yi and Oh, 2015), aldehyde dehydrogenase (Yi and Oh, 2015;Singh et al, 2015), and NQO1 (Awadallah et al, 2008) have been identified in several PDAC cell lines. Many of these drug-metabolizing enzymes as well as the antioxidant systems require NADPH as a cofactor, and Nrf2 regulates all four of the NADPH-generating enzymes.…”

Association between aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism and susceptibility to colorectal cancer: a meta-analysis

“…A possible reason for this may be that ALDH2 is a major acetaldehyde-metabolizing enzyme, and its inactivation because of the Glu/Lys genotype leads to acetaldehyde accumulation, which in turn could lead to a series of symptoms that may prevent alcohol consumption (Yang et al, 2009). In addition, the potential function of the ALDH2 Glu504Lys polymorphism could be affected by gene-gene and gene-environment interactions (Singh et al, 2015). Therefore, caution should be exercised when considering this conclusion.…”