RRC ID 21902
Author Ohsawa S, Sato Y, Enomoto M, Nakamura M, Betsumiya A, Igaki T.
Title Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila.
Journal Nature
Abstract Mitochondrial respiratory function is frequently impaired in human cancers. However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras-activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras.
Volume 490(7421)
Pages 547-51
Published 2012-10-25
DOI 10.1038/nature11452
PII nature11452
PMID 23023132
MeSH Animals Cell Transformation, Neoplastic Clone Cells / metabolism Clone Cells / pathology Compound Eye, Arthropod / growth & development Compound Eye, Arthropod / pathology Compound Eye, Arthropod / ultrastructure Disease Models, Animal Disease Progression* Drosophila Proteins / metabolism* Drosophila melanogaster / cytology* Drosophila melanogaster / enzymology Drosophila melanogaster / genetics Drosophila melanogaster / metabolism* Imaginal Discs / metabolism Imaginal Discs / pathology Intracellular Signaling Peptides and Proteins / metabolism* JNK Mitogen-Activated Protein Kinases / metabolism Mitochondria / metabolism Mitochondria / pathology* Neoplasms / metabolism Neoplasms / pathology* Oncogene Protein p21(ras) / genetics Oncogene Protein p21(ras) / metabolism Oxidative Stress Protein-Serine-Threonine Kinases / metabolism* Reactive Oxygen Species / metabolism Signal Transduction* Transcription Factors / metabolism Up-Regulation Wnt1 Protein / metabolism
IF 41.577
Times Cited 77
Drosophila 5993R-1 5993R-2 4889R-3 4889R-4 pdswk10101 CG9140KG01287 CG11455d08265 RFeSPk11704 mRpL4k16084 mRpL13/CG10602f0419 mRpL24f6692 mRpL17KG06809 Df(1)BSC352 and osupd-4