Phosphoinositide-specific phospholipase Cγ1 inhibition induces autophagy in human colon cancer and hepatocellular carcinoma cells.
Phosphoinositide-specific phospholipase Cγ1 inhibition induces autophagy in human colon cancer and hepatocellular carcinoma cells.
复制标题
磷酸肌醇特异性磷脂酶 C gamma 1 抑制诱导人结肠癌和肝细胞癌细胞自噬
DOI：
10.1038/s41598-017-13334-y
复制
发表时间：
2017-10-24
影响因子：
4.6
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Dai L;Chen X;Lu X;Wang F;Zhan Y;Song G;Hu T;Xia C;Zhang B
磷脂酰肌醇特异性磷脂酶C（PLC）γ1（Phosphoinositide-specific phospholipase C，PLC γ1）参与肿瘤细胞的增殖和转移。然而，PLCγ1是否调节自噬及其机制尚不清楚。本研究探讨了PLCγ1与人结肠癌细胞系HCT 116和肝癌细胞系HepG 2自噬的关系。结果表明，通过慢病毒介导的shRNA/PLCγ1转染或pRK 5-PLCγ1（Y 783 A）载体瞬时转染抑制PLCγ1可增加LC 3B-II水平和自噬空泡数量，降低p62水平。添加自噬抑制剂导致LC 3B和p62积累。AMPK的激活通过阻断FAK/PLCγ1轴，促进PLCγ1抑制诱导的自噬。此外，PLCγ1抑制或者阻断mTOR/ULK 1轴或者增强Beclin 1-IP 3R-Bcl-2复合物的解离以诱导自噬。综上所述，我们的研究结果表明，PLCγ1抑制诱导自噬，FAK/PLCγ1轴是AMPK激活依赖性自噬信号级联的潜在下游效应器。阻断mTOR/ULK 1轴和Beclin 1-IP 3R-Bcl-2复合物的解离都有助于PLCγ1抑制诱导自噬。因此，这些发现为PLCγ1在结肠癌和肝细胞癌细胞中调节自噬提供了新的见解。
Phosphoinositide-specific phospholipase C (PLC) γ1 has been reported to be involved in cancer cell proliferation and metastasis. However, whether PLCγ1 modulates autophagy and the underlying mechanism remains unclear. Here, we investigated the relationship between PLCγ1 and autophagy in the human colon cancer cell line HCT116 and hepatocellular carcinoma cell line HepG2. The results indicated that PLCγ1 inhibition via lentivirus-mediated transduction with shRNA/PLCγ1 or transient transfection with pRK5-PLCγ1 (Y783A) vector increased LC3B-II levels and the number of autophagic vacuoles and decreased p62 levels. Addition of an autophagy inhibitor led to LC3B and p62 accumulation. Furthermore, AMPK activation promoted the autophagy induced by PLCγ1 inhibition by blocking the FAK/PLCγ1 axis. In addition, PLCγ1 inhibition either blocked the mTOR/ULK1 axis or enhanced dissociation of the Beclin1-IP3R-Bcl-2 complex to induce autophagy. Taken together, our findings revealed that PLCγ1 inhibition induced autophagy and the FAK/PLCγ1 axis is a potential downstream effector of the AMPK activation-dependent autophagy signalling cascade. Both blockade of the mTOR/ULK1 axis and dissociation of the Beclin1-IP3R-Bcl-2 complex contributed to the induction of autophagy by PLCγ1 inhibition. Consequently, these findings provide novel insight into autophagy regulation by PLCγ1 in colon cancer and hepatocellular carcinoma cells.
登录
查看更多内容
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
影响因子：
9.7
作者：
Luo, Ming;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
影响因子：
15.9
作者：
Caino, M. Cecilia;Chae, Young Chan;Altieri, Dario C.
通讯作者：
Altieri, Dario C.
影响因子：
10.5
作者：
Karantza-Wadsworth, Vassiliki;Patel, Shyam;White, Eileen
通讯作者：
White, Eileen