Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma
Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma
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抑制主动自噬可诱导细胞凋亡并增加胆管癌的化疗敏感性
DOI：
10.1038/labinvest.2011.97
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发表时间：
2011-08-01
影响因子：
5
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
--
作者：
Hou, Yu-Jie;Dong, Li-Wei;Wang, Hong-Yang
肝内胆管细胞癌是一种起源于胆管上皮的恶性肿瘤。然而，许多胆管癌细胞显示出对化疗药物的抗性，这诱导细胞凋亡。自噬的作用和自噬相关基因的治疗价值在ICC中很大程度上未知。在这里，我们发现自噬在营养饥饿和异种移植胆管癌细胞中被激活。此外，自噬基因的表达和自噬活性在临床ICC标本高于正常胆管细胞分离的激光捕获显微切割。通过自噬抑制剂或siRNA抑制自噬，胆管癌细胞在营养饥饿期间表现出增殖延迟和凋亡增加。此外，自噬抑制剂治疗或beclin 1的敲低抑制肿瘤生长并使ICC细胞对化疗剂诱导的细胞死亡敏感。总之，我们的数据表明自噬在ICC中被激活，自噬的失活可能导致细胞凋亡并增强化疗敏感性。
Intrahepatic cholangiocellular carcinomas (ICCs) are usually fatal neoplasms originating from bile duct epithelia. However, many cholangiocarcinoma cells are shown to be resistant to chemotherapeutic drugs, which induce cell apoptosis. The role of autophagy and the therapeutic value of autophagy-associated genes are largely unknown in ICC. Here, we showed that autophagy was activated in nutrient starvation and xenograft cholangiocarcinoma cells. Furthermore, expression of autophagic genes and their autophagic activity were higher in clinical ICC specimens than that in normal cholangiocytes separated by laser capture microdissection. Inhibition of autophagy by autophagy inhibitors or siRNA, cholangiocarcinoma cells showed detention of proliferation and increase of apoptosis during nutrient starvation. In addition, autophagy inhibitor treatment or knockdown of beclin 1 suppressed tumor growth and sensitized ICC cells to chemotherapeutic agent-induced cell death. In conclusion, our data showed that autophagy is activated in ICC, and inactivation of autophagy may lead to cell apoptosis and enhance chemotherapy sensitivity.