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SA-49, a Novel Aloperine Derivative, Induces MITF-Dependent Lysosomal Degradation of PD-L1

46 Pages Posted: 4 Dec 2018

See all articles by Na Zhang

Na Zhang

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Yueying Dou

Hefei BOE Hospital Co., Ltd

Lu Liu

Qingdao University

Xin Zhang

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Xiaojia Liu

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Qingxuan Zeng

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Yang Liu

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Mingxiao Yin

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Xiujun Liu

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Danqing Song

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

Hongbin Deng

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

More...

Abstract

Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed. Here we reported that SA-49, a novel aloperine derivative, decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells. Importantly, we found lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice. Our data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function.

Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81773782, 81473248 and 81621064) and CAMS Major Collaborative Innovation Project (2016-12M-1-011).

Declaration of Interests: The authors have declared no conflicts of interest.

Ethics Approval Statement: The animal procedures were carried out with the approval of the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences.

Keywords: Aloperine; PD-L1; Lysosome; MITF; Checkpoint Inhibitors

Suggested Citation

Zhang, Na and Dou, Yueying and Liu, Lu and Zhang, Xin and Liu, Xiaojia and Zeng, Qingxuan and Liu, Yang and Yin, Mingxiao and Liu, Xiujun and Song, Danqing and Deng, Hongbin, SA-49, a Novel Aloperine Derivative, Induces MITF-Dependent Lysosomal Degradation of PD-L1 (November 26, 2018). Available at SSRN: https://ssrn.com/abstract=3294082

Na Zhang

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Yueying Dou

Hefei BOE Hospital Co., Ltd

Hefei, 230011
China

Lu Liu

Qingdao University

No. 308 Ning Xia Road
Qingdao, 266071
China

Xin Zhang

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Xiaojia Liu

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Qingxuan Zeng

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Yang Liu

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Mingxiao Yin

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Xiujun Liu

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology

China

Danqing Song

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology ( email )

China

Hongbin Deng (Contact Author)

Chinese Academy of Medical Sciences - Institute of Medicinal Biotechnology ( email )

China

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