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Manent, J., Banerjee, S., de Matos Simoes, R., Zoranovic, T., Mitsiades, C., Penninger, J.M., Simpson, K.J., Humbert, P.O., Richardson, H.E. (2017). Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species.  Oncogene 36(40): 5576--5592.
FlyBase ID
FBrf0236858
Publication Type
Research paper
Abstract
Activation of Ras signalling occurs in ~30% of human cancers; however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras (Ras(V12)) in Drosophila, we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP, correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras-driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances Ras(V12)-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in Ras(V12) clones also results in non-cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis, which might inform the development of novel therapeutics targeting Ras-driven cancers.
PubMed ID
PubMed Central ID
PMC5633656 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Oncogene
    Title
    Oncogene
    Publication Year
    1987-
    ISBN/ISSN
    0950-9232
    Data From Reference