Mitochondrial Dysfunction Inhibits Hypoxia-Induced HIF-1? Stabilization and Expression of Its Downstream Targets.

ABSTRACT: mtDNA variations often result in bioenergetic dysfunction inducing a metabolic switch toward glycolysis resulting in an unbalanced pH homeostasis. In hypoxic cells, expression of the tumor-associated carbonic anhydrase IX (CAIX) is enhanced to maintain cellular pH homeostasis. We hypothesized that cells with a dysfunctional oxidative phosphorylation machinery display elevated CAIX expression levels. Increased glycolysis was observed for cytoplasmic 143B mutant hybrid (m.3243A>G, >94.5%) cells (p < 0.05) and 143B mitochondrial DNA (mtDNA) depleted cells (p < 0.05). Upon hypoxia (0.2%, 16 h), genetic or pharmacological oxidative phosphorylation (OXPHOS) inhibition resulted in decreased CAIX (p < 0.05), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1?) expression levels. Reactive oxygen species (ROS) and prolyl-hydroxylase 2 (PHD2) levels could not explain these observations. In vivo, tumor take (>500 mm3) took longer for mutant hybrid xenografts, but growth rates were comparable with control tumors upon establishment. Previously, it has been shown that HIF-1? is responsible for tumor establishment. In agreement, we found that HIF-1? expression levels and the pimonidazole-positive hypoxic fraction were reduced for the mutant hybrid xenografts. Our results demonstrate that OXPHOS dysfunction leads to a decreased HIF-1? stabilization and subsequently to a reduced expression of its downstream targets and hypoxic fraction in vivo. In contrast, hypoxia-inducible factor 2-alpha (HIF-2?) expression levels in these xenografts were enhanced. Inhibition of mitochondrial function is therefore an interesting approach to increase therapeutic efficacy in hypoxic tumors.

SUBMITTER: van Gisbergen MW 

PROVIDER: S-EPMC7248342 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature