【摘 要】
：
Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target.RAS activation promotes autophagy, a highly regula
【机 构】
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Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
【出 处】
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The 7th International Symposium on Autophagy 2015(第七届自噬国际研讨会
论文部分内容阅读
Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target.RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses.Here we report that Casein Kinase 1 alpha (CK1c), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy.Depletion or pharmacologic inhibition of CK1α enhances autophagic flux in oncogenic RAS-driven human fibroblasts and multiple cancer cell lines.FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, is a critical target of CK1α.Oncogenic RAS increases CK1α protein abundance via PI3K-AKT-mTOR activation.CK1α phosphorylation of nuclear FOXO3A then inhibits the transactivation of genes critical for RAS-induced autophagy.Importantly, pharmacologic CK1α inactivation synergizes with lysosomotropic agents to reverse the growth of oncogenic RAS-driven cancer cells and xenografts.Targeting CK1c-regulated autophagy offers a new therapeutic opportunity to treat oncogenic Ras-driven cancers.
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