title: GSK3 is required for rapalogs to induce degradation of some oncogenic proteins and to suppress cancer cell growth.
abstract: The single-agent activity of rapalogs (rapamycin and its analogues) in most tumor types has been modest at best. The underlying mechanisms are largely unclear. In this report, we have uncovered a critical role of GSK3 in regulating degradation of some oncogenic proteins induced by rapalogs and cell sensitivity to rapalogs. The basal level of GSK3 activity was positively correlated with cell sensitivity of lung cancer cell lines to rapalogs. GSK3 inhibition antagonized rapamycin's growth inhibitory effects both in vitro and in vivo, while enforced activation of GSK3β sensitized cells to rapamycin. GSK3 inhibition rescued rapamcyin-induced reduction of several oncogenic proteins such as cyclin D1, Mcl-1 and c-Myc, without interfering with the ability of rapamycin to suppress mTORC1 signaling and cap binding. Interestingly, rapamycin induces proteasomal degradation of these oncogenic proteins, as evidenced by their decreased stabilities induced by rapamcyin and rescue of their reduction by proteasomal inhibition. Moreover, acute or short-time rapamycin treatment dissociated not only raptor, but also rictor from mTOR in several tested cell lines, suggesting inhibition of both mTORC1 and mTORC2. Thus, induction of GSK3-dependent degradation of these oncogenic proteins is likely secondary to mTORC2 inhibition; this effect should be critical for rapamycin to exert its anticancer activity.
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors: Junghui
authors: J
authors: Koo
authors: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Xuerong
authors: X
authors: Wang
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors: Taofeek K
authors: TK
authors: Owonikoko
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors: Suresh S
authors: SS
authors: Ramalingam
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors: Fadlo R
authors: FR
authors: Khuri
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors: Shi-Yong
authors: SY
authors: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008301:Maleimides / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; C473711:Chir 99021; D007211:Indoles; D008301:Maleimides; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D011725:Pyridines; D011743:Pyrimidines; C492571:RICTOR protein, human; D034741:RNA, Small Interfering; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D011993:Recombinant Fusion Proteins; D000076223:Regulatory-Associated Protein of mTOR; C417521:SB 216763; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus
keywords: GSK3; degradation; mTOR; oncogenic proteins; rapamycin