Abstract
BackgroundTo deliver efficacious personalised cancer treatment, it is essential to characterise the cellular metabolism as well as the genetic stability of individual tumours. In this study, we describe a new axis between DNA repair and detoxification of aldehyde derivatives with important implications for patient prognosis and treatment.MethodsWestern blot and qPCR analyses were performed in relevant non-transformed and cancer cell lines from lung and liver tissue origin in combination with bioinformatics data mining of The Cancer Genome Atlas database from lung and hepatocellular cancer patients.ResultsUsing both biochemical and bioinformatics approaches, we revealed an association between the levels of expression of the aldehyde detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) and the key DNA base excision repair protein XRCC1. Across cancer types, we found that if one of the corresponding genes exhibits a low expression level, the level of the other gene is increased. Surprisingly, we found that low ALDH2 expression levels associated with high XRCC1 expression levels are indicative for a poor overall survival, particularly in lung and liver cancer patients. In addition, we found that Mithramycin A, a XRCC1 expression inhibitor, efficiently kills cancer cells expressing low levels of ALDH2.ConclusionsOur data suggest that lung and liver cancers require efficient single-strand break repair for their growth in order to benefit from a low aldehyde detoxification metabolism. We also propose that the ratio of XRCC1 and ALDH2 levels may serve as a useful prognostic tool in these cancer types.
Highlights
Aldehydes are abundant organic molecules that can be assimilated from food or produced within cells as by-products of cellular metabolism
Despite an increased amount of aldehyde dehydrogenase 2 (ALDH2), we observed a slight but significant increase in DNA-protein crosslinks (DPCs) in XRCC1-deficient cells compared to control cells treated with unspecific siRNA (Fig. 1G, compare lanes 1 and 2)
We found that ALDH2 knockdown alone promotes higher survival rates for both the H1299 (Fig. 8D, column 3) and JHH4 (Fig. 8E, Fig. 5 ALDH2 and XRCC1 expression have no predictive value in oesophagus cancer. a Boxplot representing the overall variation in XRCC1 and ALDH2 mRNA levels in oesophageal cancers (Oncomine). b Kaplan-Meier analysis of the 5-year overall survival of oesophageal cancer patients (TCGA) stratified for XRCC1 mRNA levels. c Kaplan-Meier analysis of the 5-year overall survival of oesophagus cancer patients (TCGA) stratified for ALDH2 mRNA levels column 3) cells, supporting our observation that lower ALDH2 levels are advantageous for cancer cells (Fig. 2)
Summary
Aldehydes are abundant organic molecules that can be assimilated from food or produced within cells as by-products of cellular metabolism. Acetaldehyde (AcAl) is the most studied, for its importance in. Endogenous AcAl is mainly produced by the cellular processing of alcohol and as an intermediate in sugar metabolism [4]. Aldehydes are highly reactive molecules, generating a range of DNA modification products including DNA strand crosslinks and DNAprotein crosslinks [4]. Due to their toxicity, AcAls are proc-. To deliver efficacious personalised cancer treatment, it is essential to characterise the cellular metabolism as well as the genetic stability of individual tumours. We describe a new axis between DNA repair and detoxification of aldehyde derivatives with important implications for patient prognosis and treatment
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