[HTML][HTML] Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers
JK Cheong, F Zhang, PJ Chua, BH Bay… - The Journal of …, 2015 - Am Soc Clin Investig
The Journal of clinical investigation, 2015•Am Soc Clin Investig
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 1α (CK1α), a ubiquitously expressed serine/threonine kinase, is a key
negative regulator of oncogenic RAS–induced autophagy. Depletion or pharmacologic
inhibition of CK1α enhanced autophagic flux in oncogenic RAS–driven human fibroblasts …
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 1α (CK1α), a ubiquitously expressed serine/threonine kinase, is a key
negative regulator of oncogenic RAS–induced autophagy. Depletion or pharmacologic
inhibition of CK1α enhanced autophagic flux in oncogenic RAS–driven human fibroblasts …
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 1α (CK1α), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS–induced autophagy. Depletion or pharmacologic inhibition of CK1α enhanced autophagic flux in oncogenic RAS–driven human fibroblasts and multiple cancer cell lines. FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, was a critical target of CK1α, as depletion of CK1α reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1α protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1α increased phosphorylation of nuclear FOXO3A, thereby inhibiting transactivation of genes critical for RAS-induced autophagy. In both RAS-driven cancer cells and murine xenograft models, pharmacologic CK1α inactivation synergized with lysosomotropic agents to inhibit growth and promote tumor cell death. Together, our results identify a kinase feedback loop that influences RAS-dependent autophagy and suggest that targeting CK1α-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS–driven cancers.
The Journal of Clinical Investigation