HSP60 silencing promotes Warburg-like phenotypes and switches the mitochondrial function from ATP production to biosynthesis in ccRCC cells

Publication date: Available online 14 May 2019Source: Redox BiologyAuthor(s): Ruifang Teng, Zongyuan Liu, Haiping Tang, Wenhao Zhang, Yuling Chen, Renhua Xu, Liang Chen, Jiangping Song, Xiaohui Liu, Haiteng DengAbstractHSP60 is a major mitochondrial chaperone for maintaining mitochondrial proteostasis. Our previous studies showed that HSP60 was significantly downregulated in clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer characterized by the classic Warburg effect. Here, we analyzed datasets in The Cancer Genome Atlas and revealed that higher HSP60 expression correlated with better overall survival in ccRCC patients. We also stably knocked down or overexpressed HSP60 in ccRCC cells to investigate the effects of HSP60 expression on the transition between oxidative phosphorylation and glycolysis. We confirmed that HSP60 knockdown increased cell proliferation, whereas its overexpression decreased cell growth. Proteomics and metabolomics revealed that HSP60 knockdown promoted Warburg-like phenotypes with enhanced glycolysis and decreased mitochondrial activity. Consistent with this finding, isotope tracing showed that the metabolic flow from glycolysis to TCA was reduced. However, HSP60 silencing enhanced mitochondrial functions in glutamine-directed biosynthesis with increased flow in two parts of the TCA cycle: Gln→αKG→OAA→Asp and Gln→αKG→ISO→acetyl-CoA, resulting in elevated de novo nucleotide synthesis and lipid synthesis. Proteom...
Source: Redox Biology - Category: Biology Source Type: research