PMID- 31316145 OWN - NLM STAT- MEDLINE DCOM- 20200128 LR - 20220727 IS - 1476-5594 (Electronic) IS - 0950-9232 (Linking) VI - 38 IP - 35 DP - 2019 Aug TI - Inhibition of mTOR complex 1/p70 S6 kinase signaling elevates PD-L1 levels in human cancer cells through enhancing protein stabilization accompanied with enhanced beta-TrCP degradation. PG - 6270-6282 LID - 10.1038/s41388-019-0877-4 [doi] AB - The involvement of mammalian target of rapamycin (mTOR) in the positive regulation of oncogenesis has been well documented and thus mTOR has emerged as an attractive cancer therapeutic target. Although rapamycin and its analogues (rapalogs) are FDA-approved for the treatment of certain cancers, major success in targeting mTOR, particularly with new generation mTOR kinase inhibitors, for the effective treatment of cancers has not been achieved. Hence, a thorough understanding of the biology of the mTOR axis in cancer is still needed. It is now recognized that programmed death-ligand 1 (PD-L1) expression on cancer cells is a critical mechanism contributing to immunosuppression and immune escape via interacting with program death-1 (PD-1) on immune cells. This study has revealed a previously undiscovered role of the mTOR complex 1 (mTORC1)/p70 S6 kinase (p70S6K) in the negative regulation of PD-L1 on cancer cells and tissues. We demonstrate that disruption of this signaling pathway with mTOR inhibitors, raptor knockdown or p70S6K inhibitors elevated PD-L1 levels in some lung and other cancer cell lines. Elevation of PD-L1 by inhibition of mTORC1/p70S6K signaling is likely due to suppression of beta-TrCP-mediated proteasomal degradation of PD-L1, because inhibition of either mTORC1 or p70S6K facilitated beta-TrCP degradation accompanied with enhanced PD-L1 protein stabilization. Our current findings indicate the complexity of the mTOR axis in cancer, which should be considered when targeting this axis for effective cancer treatment. Our findings also suggest a strong scientific rationale for enhancing PD-1/PD-L1-targeted cancer immunotherapy through co-targeting mTORC1/p70S6K signaling. FAU - Deng, Liang AU - Deng L AD - Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China. AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. FAU - Qian, Guoqing AU - Qian G AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. FAU - Zhang, Shuo AU - Zhang S AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. AD - First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China. FAU - Zheng, Hongmei AU - Zheng H AD - Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China. FAU - Fan, Sonqing AU - Fan S AD - Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China. FAU - Lesinski, Gregory B AU - Lesinski GB AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. FAU - Owonikoko, Taofeek K AU - Owonikoko TK AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. FAU - Ramalingam, Suresh S AU - Ramalingam SS AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. FAU - Sun, Shi-Yong AU - Sun SY AD - Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. ssun@emory.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190717 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one) RN - 0 (B7-H1 Antigen) RN - 0 (Benzoxazoles) RN - 0 (CD274 protein, human) RN - 0 (Enzyme Inhibitors) RN - 0 (Leupeptins) RN - 0 (Morpholines) RN - 0 (Naphthyridines) RN - 0 (Pyrimidines) RN - 0 (beta-Transducin Repeat-Containing Proteins) RN - 970JJ37FPW ((5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol) RN - 98600C0908 (Cycloheximide) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - JGH0DF1U03 (sapanisertib) RN - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - A549 Cells MH - B7-H1 Antigen/genetics/*metabolism MH - Benzoxazoles/pharmacology MH - Cycloheximide/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Gene Expression Regulation, Neoplastic/drug effects MH - HCT116 Cells MH - HEK293 Cells MH - Humans MH - Leupeptins/pharmacology MH - MCF-7 Cells MH - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors/metabolism MH - Morpholines/pharmacology MH - Naphthyridines/pharmacology MH - Neoplasms/genetics/*metabolism/pathology MH - Protein Stability/drug effects MH - Pyrimidines/pharmacology MH - Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors/metabolism MH - Signal Transduction/drug effects/genetics MH - *Sirolimus/analogs & derivatives/pharmacology MH - Tumor Cells, Cultured MH - beta-Transducin Repeat-Containing Proteins/*metabolism EDAT- 2019/07/19 06:00 MHDA- 2020/01/29 06:00 CRDT- 2019/07/19 06:00 PHST- 2019/01/07 00:00 [received] PHST- 2019/06/26 00:00 [accepted] PHST- 2019/06/18 00:00 [revised] PHST- 2019/07/19 06:00 [pubmed] PHST- 2020/01/29 06:00 [medline] PHST- 2019/07/19 06:00 [entrez] AID - 10.1038/s41388-019-0877-4 [pii] AID - 10.1038/s41388-019-0877-4 [doi] PST - ppublish SO - Oncogene. 2019 Aug;38(35):6270-6282. doi: 10.1038/s41388-019-0877-4. Epub 2019 Jul 17.