Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma Cells via Inhibiting CDK4-RB Pathway
Wogonin Induces Apoptosis and Reverses Sunitinib Resistance of Renal Cell Carcinoma Cells via Inhibiting CDK4-RB Pathway
复制标题
汉黄芩素通过抑制CDK4-RB途径诱导细胞凋亡并逆转肾细胞癌细胞舒尼替尼耐药
DOI：
10.3389/fphar.2020.01152
复制
发表时间：
2020-07-24
影响因子：
5.6
通讯作者：
Shi, Benkang
中科院分区：
文献类型：
--
作者：
Wang, Yong;Chen, Shouzhen;Shi, Benkang
汉黄芩素是从黄芩中提取的有效成分，对多种恶性肿瘤具有抗肿瘤作用。然而，汉黄芩素在肾细胞癌细胞中的作用仍然是难以捉摸的。本研究旨在探讨汉黄芩素对肾癌细胞的作用及其机制。汉黄芩素对肾细胞癌细胞系786-O和OS-RC-2有明显的细胞毒作用，而对人胚肾细胞系HEK-293细胞的细胞毒作用较弱。汉黄芩素处理显着抑制肾癌细胞的增殖，迁移和侵袭。我们进一步发现，通过抑制CDK 4-RB途径，汉黄芩素下调CDC 6的转录，干扰DNA复制，诱导DNA损伤和细胞凋亡在RCC细胞。此外，我们发现在舒尼替尼耐药的786-O、OS-RC-2和TK-10细胞中，p-RB、CDK 4和Cyclin D1的水平上调，palbociclib或汉黄芩素抑制CDK 4可有效逆转舒尼替尼耐药，表明CDK 4-RB通路的过度活化可能至少部分导致RCC对舒尼替尼的耐药。总之，我们的研究结果表明汉黄芩素可以通过抑制CDK 4-RB通路诱导RCC细胞凋亡并逆转RCC细胞的舒尼替尼耐药，从而表明在RCC患者的未来管理中具有潜在的治疗意义。
Wogonin, an active component derived from Scutellaria baicalensis, has shown anti-tumor activities in several malignancies. However, the roles of wogonin in RCC cells remain elusive. Here, we explored the effects of wogonin on RCC cells and the underlying mechanisms. We found that wogonin showed significant cytotoxic effects against RCC cell lines 786-O and OS-RC-2, with much lower cytotoxic effects on human normal embryonic kidney cell line HEK-293 cells. Wogonin treatment dramatically inhibited the proliferation, migration, and invasion of RCC cells. We further showed that by inhibiting CDK4-RB pathway, wogonin transcriptionally down-regulated CDC6, disturbed DNA replication, induced DNA damage and apoptosis in RCC cells. Moreover, we found that the levels of p-RB, CDK4, and Cyclin D1 were up-regulated in sunitinib resistant 786-O, OS-RC-2, and TK-10 cells, and inhibition of CDK4 by palbociclib or wogonin effectively reversed the sunitinib resistance, indicating that the hyperactivation of CDK4-RB pathway may at least partially contribute to the resistance of RCC to sunitinib. Together, our findings demonstrate that wogonin could induce apoptosis and reverse sunitinib resistance of RCC cellsviainhibiting CDK4-RB pathway, thus suggesting a potential therapeutic implication in the future management of RCC patients.