Maintaining Glycogen Synthase Kinase-3 Activity Is Critical for mTOR Kinase Inhibitors to Inhibit Cancer Cell Growth

• Type of Material: Article
• Authors: Junghui Koo, Emory University; Ping Yue, Emory University; Anthony A. Gal, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2014-05-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-13-2946
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 74
• Issue: 9
• Start Page: 2555
• End Page: 2568
• Grant/Funding Information: This work was supported by NIH R01 CA118450 (S.-Y. Sun), R01 CA160522 (S.-Y. Sun), and P01 CA116676 (project 1; F.R. Khuri and S.-Y. Sun).
• Keywords: Science & Technology; MAMMALIAN TARGET; LUNG-CANCER; ACTIVATION; CELECOXIB-INDUCED APOPTOSIS; RAPAMYCIN; DOWN-REGULATION; GSK3; Life Sciences & Biomedicine; COMPLEX 2; Oncology; AKT PHOSPHORYLATION; CYCLIN D1 DEGRADATION
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology; Health Sciences, Epidemiology

Abstract

mTOR kinase inhibitors that target both mTORC1 and mTORC2 are being evaluated in cancer clinical trials. Here, we report that glycogen synthase kinase-3 (GSK3) is a critical determinant for the therapeutic response to this class of experimental drugs. Pharmacologic inhibition of GSK3 antagonized their suppressive effects on the growth of cancer cells similarly to genetic attenuation of GSK3. Conversely, expression of a constitutively activated form of GSK3β sensitized cancer cells to mTOR inhibition. Consistent with these findings, higher basal levels of GSK3 activity in a panel of human lung cancer cell lines correlated with more efficacious responses. Mechanistic investigations showed that mTOR kinase inhibitors reduced cyclin D1 levels in a GSK3β-dependent manner, independent of their effects on suppressing mTORC1 signaling and cap binding. Notably, selective inhibition of mTORC2 triggered proteasome-mediated cyclin D1 degradation, suggesting that mTORC2 blockade is responsible for GSK3-dependent reduction of cyclin D1. Silencing expression of the ubiquitin E3 ligase FBX4 rescued this reduction, implicating FBX4 in mediating this effect of mTOR inhibition. Together, our findings define a novel mechanism by which mTORC2 promotes cell growth, with potential implications for understanding the clinical action of mTOR kinase inhibitors.