Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein-coupled Receptor 68.

Abstract

Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca alkaloid obtained from Ervatamia microphylla leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues in vitro and in vivo Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs in vivo showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.

• Authors: Takahiro Yamanaka, Norifumi Harimoto, Takehiko Yokobori, Ryo Muranushi, Kouki Hoshino, Kei Hagiwara, Dolgormaa Gantumur, Tadashi Handa, Norihiro Ishii, Mariko Tsukagoshi, Takamichi Igarashi, Akira Watanabe, Norio Kubo, Kenichiro Araki, Kazuo Umezawa, Ken Shirabe
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 6 Pg. 1019-1028 (06 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 33722852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• GPR68 protein, human
• Receptors, G-Protein-Coupled
• Vinca Alkaloids
• conophylline

Topics

• Animals
• Cancer-Associated Fibroblasts (metabolism)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Male
• Mice
• Receptors, G-Protein-Coupled (metabolism)
• Vinca Alkaloids (pharmacology, therapeutic use)