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

Marike W. van Gisbergen, Kelly Offermans, An M. Voets, Natasja G. Lieuwes, Rianne Biemans, Roland F. Hoffmann, Ludwig J. Dubois*, Philippe Lambin

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    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 alpha) expression levels. Reactive oxygen species (ROS) and prolyl-hydroxylase 2 (PHD2) levels could not explain these observations. In vivo, tumor take (>500 mm(3)) took longer for mutant hybrid xenografts, but growth rates were comparable with control tumors upon establishment. Previously, it has been shown that HIF-1 alpha is responsible for tumor establishment. In agreement, we found that HIF-1 alpha 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 alpha 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 alpha) expression levels in these xenografts were enhanced. Inhibition of mitochondrial function is therefore an interesting approach to increase therapeutic efficacy in hypoxic tumors.

    Original languageEnglish
    Article number770
    Number of pages12
    JournalFrontiers in Oncology
    Volume10
    DOIs
    Publication statusPublished - 19-May-2020

    Keywords

    • mtDNA
    • mitochondria
    • OXPHOS
    • CAIX
    • HIF-1 alpha
    • Metformin
    • OXIDATIVE STRESS
    • COMPLEX I
    • METFORMIN
    • CANCER
    • CELLS
    • HIF-1
    • GENE
    • HETEROGENEITY
    • SIRT3
    • ROS

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