Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, China.
Department of General Surgery, Shenzhen Luohu People's Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518000, China.
Cancer Lett. 2018 Nov 1;436:129-138. doi: 10.1016/j.canlet.2018.08.010. Epub 2018 Aug 15.
Gemcitabine is the cornerstone of pancreatic cancer treatment. Although effective in most patients, development of tumor resistance to gemcitabine can critically limit its efficacy. The mechanisms responsible for this phenomenon remain elusive, but evidence suggests that ubiquitin-specific peptidases (USPs) may be key regulators in cancer chemo-resistance. The present study aimed to investigate the role of USP9X in gemcitabine resistance using in vitro pancreatic cell lines and a mouse xenograft model. We found that the expression of USP9X in pancreatic cancer cells was positively correlated with gemcitabine resistance, and that inhibition of USP9X by WP1130 sensitized pancreatic cancer cells to gemcitabine. Gemcitabine induced autophagy, and blocking autophagy with chloroquine improved sensitivity to gemcitabine. We also found that WP1130 inhibited gemcitabine-induced autophagy, and blocking autophagy abolished the sensitization effect of WP1130 on gemcitabine in pancreatic cancer cells. Finally, combined gemcitabine and WP1130 treatment enhanced the anti-tumor effect of gemcitabine by suppressing autophagy in vivo. Taken together, these results demonstrate that inhibition of USP9X sensitized pancreatic cancer cells to gemcitabine by inhibiting autophagy, which provides a novel insight into gemcitabine resistance in pancreatic cancer.
吉西他滨是胰腺癌治疗的基石。虽然它对大多数患者有效，但肿瘤对吉西他滨的耐药性发展可能会严重限制其疗效。导致这种现象的机制仍不清楚，但有证据表明，泛素特异性肽酶（USPs）可能是癌症化疗耐药性的关键调节因子。本研究旨在使用体外胰腺细胞系和小鼠异种移植模型研究 USP9X 在吉西他滨耐药中的作用。我们发现，胰腺癌细胞中 USP9X 的表达与吉西他滨耐药呈正相关，USP9X 的抑制物 WP1130 可使胰腺癌细胞对吉西他滨敏感。吉西他滨诱导自噬，用氯喹阻断自噬可提高吉西他滨的敏感性。我们还发现 WP1130 抑制吉西他滨诱导的自噬，阻断自噬可消除 WP1130 对胰腺癌细胞中吉西他滨的增敏作用。最后，联合使用吉西他滨和 WP1130 治疗通过抑制自噬增强了吉西他滨在体内的抗肿瘤作用。综上所述，这些结果表明，抑制 USP9X 通过抑制自噬使胰腺癌细胞对吉西他滨敏感，为胰腺癌中吉西他滨耐药性提供了新的见解。
