PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth.

PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth. Am J Physiol Cell Physiol. 2015 Mar 25;:ajpcell.00322.2014 Authors: Abu Aboud O, Donohoe D, Bultman S, Fitch M, Riiff T, Hellerstein M, Weiss RH Abstract Kidney cancer (RCC) is the 6(th) most common cancer in the US and its incidence is increasing. The current progression-free survival for patients with advanced RCC rarely extends beyond 1-2 years due to the development of therapeutic resistance. We previously identified PPARα as a potential therapeutic target for this disease and showed that a specific PPARα antagonist, GW6471, induced both apoptosis and cell cycle arrest at G0/G1 in RCC cell lines associated with attenuation of cell cycle regulatory proteins. We now extend that work and show that PPARα inhibition attenuates components of RCC metabolic reprogramming capitalizing on the Warburg effect. The specific PPARα inhibitor GW6471, as well as an siRNA specific to PPARα, attenuate the enhanced fatty acid oxidation and oxidative phosphorylation associated with glycolysis inhibition, and PPARα antagonism also blocks the enhanced glycolysis which has been observed in RCC cells; this effect did not occur in normal human kidney epithelial cells. Such cell type-specific glycolysis inhibition corresponds with changes in protein levels of the oncogene c-Myc and has promising clinical implications. Furthermore, we sho...
Source: Am J Physiol Cell Ph... - Category: Cytology Authors: Tags: Am J Physiol Cell Physiol Source Type: research