1. Academic Validation
  2. Boningmycin induces AMPK-mediated endoplasmic reticulum-associated degradation of PD-L1 protein in human cancer cells

Boningmycin induces AMPK-mediated endoplasmic reticulum-associated degradation of PD-L1 protein in human cancer cells

  • Int Immunopharmacol. 2023 Sep 15;124(Pt A):110905. doi: 10.1016/j.intimp.2023.110905.
Juan Zhang 1 Jincai Wang 2 Yue Shang 3 Yang Chen 3 Shuzhen Chen 4 Qiyang He 5
Affiliations

Affiliations

  • 1 Key Laboratory of Nano-imaging and Drug-loaded Preparation of Shanxi Province, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China. Electronic address: cmuzhangjuan@163.com.
  • 2 The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100050, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100050, China. Electronic address: bjcsz@imb.pumc.edu.cn.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100050, China. Electronic address: heqiyang@imb.pumc.edu.cn.
Abstract

Anti-PD-1/PD-L1 monoclonal Antibodies have displayed remarkable clinical benefits and revolutionized the treatment of multiple tumor types, but the low response rates and immune-related adverse events limit their application, which promoting the development of small molecule agents to improve the efficacy of PD-1/PD-L1 blockade therapy. Boningmycin (BON), a new small molecule belonging to bleomycin (BLM) family, exhibits potent Anticancer activity in vitro and in vivo, as well as negligible lung toxicity, thereby can be an alternative of BLM. However, understandings about the Anticancer mechanism of BLM-related compounds are extremely rare, it remains unclear if they affect PD-L1 level in a manner similar to that of other antitumor drugs. In this study, we discover that BON significantly reduces PD-L1 protein level in NCI-H460 and HT-1080 cells. Meanwhile, BON decreases the protein level of PD-L1 in a tumor xenograft model of NCI-H460 cells. Nevertheless, the mRNA level is not influenced after BON exposure. Furthermore, BON-induced PD-L1 reduction is proteasome- dependent. By using specific inhibitors and RNA interference technology, we confirm that the decline of PD-L1 protein by BON is mediated by AMPK-activated endoplasmic reticulum-associated degradation pathway, which is like to the action of metformin. Last but not the least, BON has synergism on gefitinib in vitro and in vivo. In conclusion, it is the first report demonstrating that BON decreases PD-L1 protein level through AMPK-mediated endoplasmic reticulum-associated degradation pathway. These findings will benefit the clinical transformation of BON and aid in the elucidation of molecular mechanism of BLM-related compounds.

Keywords

AMPK; Bleomycin; Boningmycin; Endoplasmic reticulum-associated degradation pathway; PD-L1.

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