Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Rao, S; Mondragón, L; Pranjic, B; Hanada, T; Stoll, G; Köcher, T; Zhang, P; Jais, A; Lercher, A; Bergthaler, A; Schramek, D; Haigh, K; Sica, V; Leduc, M; Modjtahedi, N; Pai, TP; Onji, M; Uribesalgo, I; Hanada, R; Kozieradzki, I; Koglgruber, R; Cronin, SJ; She, Z; Quehenberger, F; Popper, H; Kenner, L; Haigh, JJ; Kepp, O; Rak, M; Cai, K; Kroemer, G; Penninger, JM.
AIF-regulated oxidative phosphorylation supports lung cancer development.
Cell Res. 2019;
Doi: 10.1038/s41422-019-0181-4
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- Co-Autor*innen der Med Uni Graz
- Kenner Lukas
- Popper Helmuth
- Quehenberger Franz
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- Abstract:
- Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a KrasG12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of KrasG12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout KrasG12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.