Abstract
The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. Here we identify an ATP-binding motif within the NADPH oxidase isoform, NOX4, and show that ATP directly binds and negatively regulates NOX4 activity. We find that NOX4 localizes to the inner mitochondria membrane and that subcellular redistribution of ATP levels from the mitochondria act as an allosteric switch to activate NOX4. We provide evidence that NOX4-derived reactive oxygen species (ROS) inhibits P300/CBP-associated factor (PCAF)-dependent acetylation and lysosomal degradation of the pyruvate kinase-M2 isoform (PKM2). Finally, we show that NOX4 silencing, through PKM2, sensitizes cultured and ex vivo freshly isolated human-renal carcinoma cells to drug-induced cell death in xenograft models and ex vivo cultures. These findings highlight yet unidentified insights into the molecular events driving cancer evasive resistance and suggest modulation of ATP levels together with cytotoxic drugs could overcome drug-resistance in glycolytic cancers.
Highlights
The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear
We examined the primary sequence of NOX4
341–561 cells with von Hippel–Lindau (VHL) reintroduced and in 786-O cells cultured in glucose or galactose where we find the latter of each condition enhances adenosine triphosphate (ATP) levels in the mitochondria concomitant with reduced NOX4 activity (Supplementary Fig. 6a, b)
Summary
The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. We find that shRNA- and siRNAmediated knockdown of NOX4 reduces ROS generation within the mitochondrial compartment in 786-O and A498 cells compared to control transfected cells (Supplementary Fig. 4d).
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