Zeitschriftenaufsatz | 2019 Open Access

AIF-regulated oxidative phosphorylation supports lung cancer development

Autor:in
Rao, Shuan; Martinez, Laura; Pranjic, Blanka; Hanada, Toshikatsu; STOLL, G; Koecher, Thomas; Zhang, Peng; Jais, Alexander; Lercher, Alexander; Bergthaler, Andreas; Schramek, Daniel; Haigh, Katharina; Sica, Valentina; Leduc, Marion; MODJTAHEDI, Nazanine; Pai, Tsung-Pin; Onji, Masahiro; Uribesalgo, Iris; Hanada, Reiko; Kozieradzki, Ivona; Koglgruber, Rubina; Cronin, Shane; She, Zhi-Gang; Quehenberger, Franz; Popper, Helmut; Kenner, Lukas; Jonathan Haigh, Jody; Kepp, Oliver; Rak, Malgorzata; Cal, Kaican; KROEMER, Guido; Penninger, Josef
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Kenner, Lukas
Journal
Cell Research
Schlagwörter
APOPTOSIS-INDUCING FACTOR; MITOCHONDRIAL; PROGRESSION; ACTIVATION; MOUSE
Dokumenten­typ
Originalarbeit
CC Lizenz
CC-BY
Open Access Type
Hybrid
ISSN/eISSN
1001-0602 - 1748-7838
DOI
Öffnen URL 10.1038/s41422-019-0181-4
WoS ID
Öffnen URL WOS:000473324700009
PubMed ID
Öffnen URL MEDLINE:31133695

Weitere Details

Band
29
Startseite
579
Letzte Seite
591
Nummer
7
Seiten­anzahl
13
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 Kras(G12D)-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 Kras(G12D)-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 Kras(G12D) 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.

Download
 RDF/XML-Format
 JSON-LD-Format
 Turtle-Format
 N3-Format