CS-33: DISCOVERY OF A p53-INDEPENDENT SUPPRESSOR OF SENESCENCE OF GLIOBLASTOMA MULTIFORME

Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor and resistant to cell senescence. Through proteomic screening we have identified a novel type of kinase, tentatively named, SSK1 (Super Signaling Kinase-1) that could connect cellular metabolism to cell growth. Depletion of SSK1 induced cellular senescence and diminished GBM cell growth in vitro and in a xenograft tumor model. The senescence caused by SSK1 depletion was accompanied by the induction of p21^WAF1/CIP1, a critical inducer of cell senescence. Importantly, p21^WAF1/CIP1 induction was independent of p53, reactive oxygen species (ROS) status, and DNA damage response pathways. Critically, the kinase activity of SSK1 is indispensable for GBM to suppress the induction of p21^WAF1/CIP1 and escape senescence. Through chemical library screening, we identified a small molecule, which inhibited SSK1 activity in vitro and in vivo. Treatment of SSK1 inhibitor increased p21^WAF1/CIP1 and triggered GBM senescence. Our data reveal a novel p21^WAF1/CIP1 regulatory pathway mediated by SSK1, which is essential for GBM to suppress senescence, and suggest a novel therapy for their treatment, pharmacologically targeting SSK1.