2. Academic Validation
  3. GPR108 is required for gambogic acid inhibiting NF-κB signaling in cancer

GPR108 is required for gambogic acid inhibiting NF-κB signaling in cancer

  • Pharmacol Res. 2022 Aug;182:106279. doi: 10.1016/j.phrs.2022.106279.
Song Lyu 1,  Xue Zhang 1,  Zhenzhen Tu 2,  Haisheng Zhou 2,  Xisong Ke 3,  Yi Qu 4
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Department of Biochemistry and Molecular Biology, Anhui Medical University, No. 69 Mei Shan Road, Hefei, China.
  • 3 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: xisongke@shutcm.edu.cn.
  • 4 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: yiqu@shutcm.edu.cn.
PMID: 35659621 DOI: 10.1016/j.phrs.2022.106279
Abstract

GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of Cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of Cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for Cancer therapy.

Keywords

Cancer; G protein-coupled receptors; GPR108; Gambogic acid; NF-κB.

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