Suppression of PGC-1? Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma.

ABSTRACT: Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1?, a central regulator of energy metabolism, is suppressed in VHL-deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC-1? suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC-1? expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1? exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1? expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1? recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1? expression as a therapeutic modality for the treatment of ccRCC.

SUBMITTER: LaGory EL 

PROVIDER: S-EPMC4518559 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature