Chen Shao-Hua, Li Dong-Liang, Yang Fang, Wu Zhe, Zhao Yong-Yang, Jiang Yi
Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
Department of Hepatobiliary Medicine, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, China.
Biochimie. 2014 Aug;103:71-9. doi: 10.1016/j.biochi.2014.04.004. Epub 2014 Apr 13.
The pancreatic adenocarcinoma remains the most aggressive human malignancy with an extremely low 5-year overall survival. Postoperative gemcitabine could significantly delay recurrence after complete resection of pancreatic cancer. However, the underlying mechanisms are not fully understood. The chemo-resistance factors against gemcitabine still need further characterizations. Here we studied the mechanism of gemcitabine-induced pancreatic cancer cell death by focusing on mammalian sterile 20-like kinase 1 (MST1) and cyclophilin D (Cyp-D). We found that MST1 and Cyp-D expressions were significantly lower in gemcitabine-resistant pancreatic cancer tissues and cell lines. In vitro, gemcitabine activated MST1 through reactive oxygen species (ROS) production, which was prevented by antioxidant n-acetyl-cysteine (NAC). We found that gemcitabine-activated MST1 translocated to mitochondria and formed a complex with the local protein Cyp-D. Gemcitabine-induced cell death was alleviated by MST1 or Cyp-D shRNA silencing, but was aggravated by MST1 or Cyp-D over-expression. Further, cyclosporin A (CsA), the Cyp-D inhibitor, prevented gemcitabine-induced MST1/Cyp-D mitochondrial complexation and cancer cell death. We suggest that gemcitabine-induced death of pancreatic cancer cells requires MST1/Cyp-D mitochondrial complexation.
胰腺腺癌仍然是最具侵袭性的人类恶性肿瘤，其5年总生存率极低。术后使用吉西他滨可显著延迟胰腺癌完全切除后的复发。然而，其潜在机制尚未完全明确。针对吉西他滨的化疗耐药因素仍需进一步明确。在此，我们通过聚焦哺乳动物不育20样激酶1（MST1）和亲环素D（Cyp-D）来研究吉西他滨诱导胰腺癌细胞死亡的机制。我们发现，在吉西他滨耐药的胰腺癌组织和细胞系中，MST1和Cyp-D的表达显著降低。在体外，吉西他滨通过产生活性氧（ROS）激活MST1，而抗氧化剂N-乙酰半胱氨酸（NAC）可阻止这一过程。我们发现，吉西他滨激活的MST1转位至线粒体，并与局部蛋白Cyp-D形成复合物。MST1或Cyp-D的短发夹RNA（shRNA）沉默可减轻吉西他滨诱导的细胞死亡，但MST1或Cyp-D的过表达则会加剧这种死亡。此外，亲环素D抑制剂环孢素A（CsA）可阻止吉西他滨诱导的MST1/Cyp-D线粒体复合以及癌细胞死亡。我们认为，吉西他滨诱导的胰腺癌细胞死亡需要MST1/Cyp-D线粒体复合。
