VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2

Abstract

The von Hippel-Lindau (VHL) is deficient in ∼70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of −130 bp to −160 bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4α). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4α and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients.

A phenomics-based approach for the detection and interpretation of shared genetic influences on 29 biochemical indices in Chinese south men

“…HCY, a naturally occurring amino acid found in blood plasma, plays the central role in biochemical indices by connecting with 23 traits. High levels of HCY have proved to associate with several body dysfunction, such as the vasculature [26] and endothelial injury [27]. Interesting, Vitamin B12 was identify its central role in biochemical indices network through correlating with 21 other traits.…”

“…ALDH2 belongs to the aldehyde dehydrogenase family of proteins, which is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 dysfunction will lead to several disease, such as cancer [27,31], alcoholic fatty liver [32], cardiovascular diseases [33]. BRAP is a cytoplasmic protein which can bind to the nuclear localization signal of BRCA1 and other proteins [34].…”

A phenomics-based approach for the detection and interpretation of shared genetic influences on 29 biochemical indices in southern Chinese men

“…HCY, a naturally occurring amino acid found in blood plasma, plays a central role in biochemical indices by connecting with 23 traits. High levels of HCY have been associated with several body dysfunctions, such as vasculature [32] and endothelial injury [33].…”

Annonaceous acetogenin mimic AA005 suppresses human colon cancer cell growth in vivo through downregulation of Mcl-1

“…Directed induction of cell death could offer therapeutic benefits for cancer treatment. Such treatments primarily target the caspase pathways to induce apoptosis [26,[38][39][40]. However, caspase activation might be dispensable for certain types of apoptosis, and increasing attention has been drawn to key molecules involved in non-apoptotic cell death or caspase-independent apoptosis [41][42][43][44][45][46][47][48].…”