Casein kinase 1α-dependent feedback loop controls autophagy in RAS-driven cancers

The Journal of Clinical Investigation
Jit Kong CheongDavid M Virshup

Abstract

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...Continue Reading

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Citations

Feb 20, 2016·Cellular and Molecular Life Sciences : CMLS·Fuquan Zhang, Jit Kong Cheong
Jun 18, 2016·Molecular & Cellular Oncology·Jit Kong Cheong, David M Virshup
Mar 24, 2015·The Journal of Clinical Investigation·Ravi K Amaravadi
Mar 30, 2018·Nature Cell Biology·Junchao CaiMengfeng Li
Sep 26, 2017·Oncogene·F ZhangJ K Cheong
May 28, 2019·Cell Death Discovery·Marilena CarrinoFrancesco Piazza
Mar 8, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Leonidas BenetatosGeorge Vartholomatos
Aug 23, 2020·International Journal of Molecular Sciences·Chen ShenDavid J Robbins
May 26, 2018·Cell Communication and Signaling : CCS·Shaojie JiangXiaoming Yang
Mar 30, 2018·Nature Cell Biology·Ivana Hermanova, Arkaitz Carracedo
Oct 24, 2019·Journal of Cellular Biochemistry·Wei ZhouZheng Jiang
Jul 14, 2020·Bioinformatics·Anja C GumpingerKarsten Borgwardt
Aug 11, 2019·European Journal of Medicinal Chemistry·Yuting QiaoHaopeng Sun
Dec 3, 2020·International Journal of Molecular Sciences·Pavlína JanovskáVítězslav Bryja
May 1, 2021·International Journal of Molecular Sciences·Zaira SpinelloSabrina Manni
Nov 16, 2021·ACS Chemical Biology·Po-Han ChenCraig M Crews

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Methods Mentioned

BETA
xenografts
PCR
flow cytometry
xenograft
transfection
protein assay
immunoprecipitation
confocal microscopy
transmission electron microscopy

Software Mentioned

GraphPad Prism
ImageJ
RT 2 Profiler PCR Array Data Analysis
ClustalW
MetaMorph Microscopy Automation & Image Analysis
MetaMorph Scoring
GraphPad
CalcuSyn

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