URI Is an Oncogene Amplified in Ovarian Cancer Cells and Is Required for Their Survival

SummaryAbrogation of negative feedback control represents a fundamental requirement for aberrantly activated signaling pathways to promote malignant transformation and resistance to therapy. Here we identify URI, which encodes a mitochondrial inhibitor of PP1γ and PP1γ-mediated feedback inhibition of S6K1-BAD survival signaling, as an oncogene amplified and overexpressed in ovarian cancer cell lines and human ovarian carcinomas. URI is an “addicting” oncogene selectively required for the survival of ovarian cancer cells with increased URI copy number. By constitutively detaining PP1γ in inactive complexes, URI sustains S6K1 survival signaling under growth factor–limiting conditions and mediates resistance of cells to cisplatin. Thus, oncogenic activation of URI defines an important mechanism for activating mitochondrial S6K1-BAD signaling and promoting cell survival through disabling PP1γ-dependent negative feedback inhibition.

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► Around 10% of aggressive ovarian cancers are characterized by URI amplification
► URI-amplified ovarian cancer cells are dependent on URI function for their survival
► URI disables normal feedback inhibition of S6K1 survival signaling by PP1γ
► URI oncogene mediates cisplatin- and rapamycin-resistance of ovarian cancer cells