Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

GSK-3 Modulates Cellular Responses To A Broad Spectrum Of Kinase Inhibitors

C. Thorne, Chonlarat Wichaidit, Adam D. Coster, Bruce A. Posner, L. Wu, S. Altschuler
Published 2015 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
A fundamental challenge in treating disease is identifying molecular states that affect cellular responses to drugs. Here, we focus on GSK-3, a key regulator for many of the hallmark behaviors of cancer cells. We alter GSK-3 activity in colon epithelial cells to test its role in modulating drug response. We find that GSK-3 activity broadly affects the cellular sensitivities to a panel of oncology drugs and kinase inhibitors. Specifically, inhibition of GSK-3 activity can strongly desensitize or sensitize cells to kinase inhibitors (e.g. mTOR or PLK1 inhibitors, respectively). Additionally, colorectal cancer cell lines, in which GSK-3 function is commonly suppressed, are resistant to mTOR inhibitors and yet highly sensitive to PLK1 inhibitors and this is further exacerbated by additional GSK-3 inhibition. Finally, by conducting a kinome-wide RNAi screen, we find that GSK-3 modulates the cell proliferative phenotype of a significant fraction (~35%) of the kinome, which includes ~50% of current, clinically relevant kinase-targeted drugs. Our results highlight an under-appreciated interplay of GSK-3 with therapeutically important kinases and suggest strategies for identifying disease-specific molecular profiles that can guide optimal selection of drug treatment.
This paper references
Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clinical cancer research: an official journal of the American Association for Cancer Research
D Rudolph (2009)
10.1016/0003-9861(88)90089-6
Phosphoserine as a recognition determinant for glycogen synthase kinase-3: phosphorylation of a synthetic peptide based on the G-component of protein phosphatase-1.
C. Fiol (1988)
10.1074/jbc.273.32.19929
Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway*
M. Pap (1998)
10.1002/mc.10087
Expression, localization, and activity of glycogen synthase kinase 3β during mouse skin tumorigenesis
Hugo Leis (2002)
10.1038/nmeth.2971
A simple image correction method for high-throughput microscopy
Adam D. Coster (2014)
10.1074/jbc.M900301200
An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1*
C. Thoreen (2009)
10.1016/j.devcel.2008.04.014
Polo on the Rise-from Mitotic Entry to Cytokinesis with Plk1.
M. Petronczki (2008)
10.1158/1078-0432.CCR-10-2946
Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies
D. Olmos (2011)
10.1042/BST0370217
A complex interplay between Akt, TSC2 and the two mTOR complexes.
Jingxiang Huang (2009)
10.1186/1471-2121-8-34
GSK-3 inhibitors induce chromosome instability
A. Tighe (2007)
10.1371/journal.pbio.1000038
Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2
Morris E. Feldman (2009)
10.1038/ncb1183
Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
E. Jacinto (2004)
10.1038/nature11252
Comprehensive Molecular Characterization of Human Colon and Rectal Cancer
D. M. Muzny (2012)
Phosphorylated GSK3beta-ser9 and EGFR are good prognostic factors for lung carcinomas.
H. Zheng (2007)
10.1242/jcs.00384
GSK-3: tricks of the trade for a multi-tasking kinase
B. Doble (2003)
10.1016/S1097-2765(01)00253-2
A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation.
S. Frame (2001)
10.1016/S0092-8674(02)00685-2
Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism
C. Liu (2002)
10.1038/nchembio.453
Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
C. Thorne (2010)
10.1016/J.DEVCEL.2007.04.001
Functional redundancy of GSK-3α and GSK-3β in wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines
B. Doble (2007)
Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. The Journal of biological chemistry
M Pap (1998)
Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines.
B. Doble (2007)
10.1016/S0959-437X(00)00120-9
GSK3, a master switch regulating cell-fate specification and tumorigenesis.
L. Kim (2000)
10.1016/j.ccr.2007.12.002
GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers.
T. Kang (2008)
10.1038/nrc1974
mTOR and cancer: insights into a complex relationship
D. Sabatini (2006)
10.1038/ncb1173
Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition
B. Zhou (2004)
10.1101/GAD.10.12.1443
The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3.
C. Yost (1996)
Regulation of Wnt signaling during adipogenesis
CN Bennett (2002)
Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
Chunming Liu (2002)
10.1016/j.cub.2004.06.054
Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton
D. Sarbassov (2004)
Direct small-molecule kinase activation: Novel approaches for a new era of drug discovery.
G. L. Simpson (2009)
10.1016/S0014-5793(99)01161-8
A GSK3‐binding peptide from FRAT1 selectively inhibits the GSK3‐catalysed phosphorylation of Axin and β‐catenin
G. M. Thomas (1999)
10.1634/theoncologist.2009-0010
Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology.
P. Schöffski (2009)
10.1158/0008-5472.CAN-05-2925
mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
Kathryn E. O'Reilly (2006)
10.1093/nar/gkq1126
DrugBank 3.0: a comprehensive resource for ‘Omics’ research on drugs
Craig Knox (2011)
10.1158/0008-5472.CAN-05-1021
Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis.
M. Farago (2005)
10.1053/j.gastro.2009.11.052
Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro.
Andres I. Roig (2010)
10.1016/J.MOLCEL.2006.09.019
S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt.
H. Zhang (2006)
10.1016/j.cell.2013.07.030
A Neo-Substrate that Amplifies Catalytic Activity of Parkinson’s-Disease-Related Kinase PINK1
Nicholas T Hertz (2013)
10.4061/2011/505607
What Are the bona fide GSK3 Substrates?
C. Sutherland (2011)
10.4161/auto.5.5.8504
Rapamycin inhibits mTORC1, but not completely
C. Thoreen (2009)
10.1126/scisignal.2001731
ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3β–Mediated Phosphorylation of Rictor
Chien-Hung Chen (2011)
10.1016/j.ceb.2009.10.007
mTOR and cancer: many loops in one pathway.
A. Efeyan (2010)
Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha
CA Thorne (2010)
10.1158/1078-0432.CCR-08-2445
BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity
D. Rudolph (2009)
Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. The oncologist
P Schoffski (2009)



This paper is referenced by
10.1101/104711
Progress Towards a Public Chemogenomic Set for Protein Kinases and a Call for Contributions
D. Drewry (2017)
10.1158/1078-0432.CCR-15-2240
Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer
A. Walz (2017)
10.1085/jgp.201812177
Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells
Michael A. Kalwat (2018)
10.1038/ncomms9390
Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method
Jia-Ren Lin (2015)
10.1371/journal.pone.0181585
Progress towards a public chemogenomic set for protein kinases and a call for contributions
D. Drewry (2017)
10.1038/ncomms10690
Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells
M. Ramirez (2016)
10.1002/anie.201603797
Discovery of a Highly Selective Glycogen Synthase Kinase-3 Inhibitor (PF-04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging.
S. Liang (2016)
10.1182/blood.2018874560
Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma.
X. Wu (2019)
10.1016/j.tranon.2017.06.003
Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models12
A. Ugolkov (2017)
10.1016/j.jcmgh.2020.04.007
Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer?
A. Prossomariti (2020)
10.1038/s41392-019-0084-3
Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9
Y. Li (2019)
10.1126/sciadv.aau9093
Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo
S. Lago (2019)
10.1016/j.bcp.2016.06.009
Xanthatin anti-tumor cytotoxicity is mediated via glycogen synthase kinase-3β and β-catenin.
Li Tao (2016)
10.17863/CAM.17148
A novel pipeline for drug discovery in neuropsychiatric disorders using high-content single-cell screening of signalling network responses ex vivo
Lago Cooke (2016)
10.1073/pnas.1902970116
Role of Polo-like kinase 1 in the regulation of the action of p31comet in the disassembly of mitotic checkpoint complexes
S. Kaisari (2019)
10.3390/ijms19124123
High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines
Shixiong Wang (2018)
10.1002/9783527683031.CH1
Global Approaches to Understanding Protein Kinase Functions
Jennifer L. Gorman (2015)
10.3389/fphar.2018.01495
GSK-3 Inhibitors and Tooth Repair: An Ethical Analysis
S. Hostiuc (2019)
10.1189/jlb.3A1216-520RR
TGF‐β inhibits IL‐7‐induced proliferation in memory but not naive human CD4+ T cells
T. P. Nguyen (2017)
10.1080/15384047.2019.1595283
Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses
I. Sahin (2019)
10.1111/jnc.15152
Glycogen synthase kinase-3ß supports serotonin transporter function and trafficking in a phosphorylation-dependent manner.
Ragu Varman Durairaj (2020)
Semantic Scholar Logo Some data provided by SemanticScholar