Mikami Daisuke, Kobayashi Mamiko, Uwada Junsuke, Yazawa Takashi, Kamiyama Kazuko, Nishimori Kazuhisa, Nishikawa Yudai, Nishikawa Sho, Yokoi Seiji, Taniguchi Takanobu, Iwano Masayuki
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-shimoaizuki, Eiheiji, Yoshida, Fukui 910-1193 Japan.
Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Ther Adv Med Oncol. 2020 Mar 20;12:1758835920913432. doi: 10.1177/1758835920913432. eCollection 2020.
Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide and establishment of new chemotherapies for HCC is urgently needed. GPR41 [free fatty acid receptor 3 (FFA3)] is a G protein-coupled receptor for short chain fatty acids, including acetate, propionate, and butyrate. In our previous study, we showed that propionate enhances the cytotoxic effect of cisplatin in HCC cells and that this mechanism is dependent on inhibition of histone deacetylases (HDACs) GPR41/FFA3. However, the antitumor action of GPR41/FFA3 has not been elucidated.
In this study, we examined AR420626 as a GPR41-selective agonist in HepG2 and HLE cells. Nude mice were used for HepG2 xenograft studies. The apoptotic effect of AR420626 was evaluated using flow cytometry analysis. Expression of apoptosis-related proteins and HDACs was evaluated by Western immunoblot. Gene silencing of HDAC 3/5/7 and GPR41 was performed using small interfering RNA. Expression of TNF-α mRNA was evaluated by TaqMan real-time polymerase chain reaction.
We found that AR420626, a selective GPR41/FFA3 agonist, suppressed growth of HepG2 xenografts and inhibited proliferation of HCC cells by inducing apoptosis. AR420626 induced proteasome activation through mTOR phosphorylation, which reduced HDAC proteins, and then increased expression of TNF-α.
AR420626, a selective GPR41/FFA3 agonist, may be a candidate as a therapeutic agent for HCC.
肝细胞癌（HCC）是全球癌症死亡的主要原因，因此迫切需要建立新的HCC化疗方法。GPR41[游离脂肪酸受体3（FFA3）]是一种G蛋白偶联受体，可识别包括乙酸盐、丙酸盐和丁酸盐在内的短链脂肪酸。在我们之前的研究中，我们发现丙酸盐可增强顺铂对HCC细胞的细胞毒性作用，且该机制依赖于对组蛋白脱乙酰酶（HDACs）GPR41/FFA3的抑制。然而，GPR41/FFA3的抗肿瘤作用尚未阐明。
在本研究中，我们检测了AR420626作为GPR41选择性激动剂在HepG2和HLE细胞中的作用。使用裸鼠进行HepG2异种移植研究。采用流式细胞术分析评估AR420626的凋亡作用。通过Western免疫印迹评估凋亡相关蛋白和HDACs的表达。使用小干扰RNA对HDAC 3/5/7和GPR41进行基因沉默。通过TaqMan实时聚合酶链反应评估TNF-α mRNA的表达。
我们发现，选择性GPR41/FFA3激动剂AR420626可抑制HepG2异种移植瘤的生长，并通过诱导凋亡抑制HCC细胞的增殖。AR420626通过mTOR磷酸化诱导蛋白酶体激活，从而减少HDAC蛋白，进而增加TNF-α的表达。
选择性GPR41/FFA3激动剂AR420626可能是一种HCC治疗药物的候选物。
