AIF-regulated oxidative phosphorylation supports lung cancer development.
Shuan Rao, Laura Mondragón, Blanka Pranjic, Toshikatsu Hanada, Gautier Stoll, Thomas Köcher, Peng Zhang, Alexander Jais, Alexander Lercher, Andreas Bergthaler, Daniel Schramek, Katharina Haigh, Valentina Sica, Marion Leduc, Nazanine Modjtahedi, Tsung-Pin Pai, Masahiro Onji, Iris Uribesalgo, Reiko Hanada, Ivona Kozieradzki, Rubina Koglgruber, Shane J Cronin, Zhigang She, Franz Quehenberger, Helmut Popper, Lukas Kenner, Jody J Haigh, Oliver Kepp, Malgorzata Rak, Kaican Cai, Guido Kroemer, Josef M Penninger
Cell research 2019 JulCancer 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.
Citation
Shuan Rao, Laura Mondragón, Blanka Pranjic, Toshikatsu Hanada, Gautier Stoll, Thomas Köcher, Peng Zhang, Alexander Jais, Alexander Lercher, Andreas Bergthaler, Daniel Schramek, Katharina Haigh, Valentina Sica, Marion Leduc, Nazanine Modjtahedi, Tsung-Pin Pai, Masahiro Onji, Iris Uribesalgo, Reiko Hanada, Ivona Kozieradzki, Rubina Koglgruber, Shane J Cronin, Zhigang She, Franz Quehenberger, Helmut Popper, Lukas Kenner, Jody J Haigh, Oliver Kepp, Malgorzata Rak, Kaican Cai, Guido Kroemer, Josef M Penninger. AIF-regulated oxidative phosphorylation supports lung cancer development. Cell research. 2019 Jul;29(7):579-591
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PMID: 31133695
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