Zhou Yang, Zhou Yunjiang, Wang Keke, Li Tao, Zhang Minda, Yang Yunjia, Wang Rui, Hu Rong
State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Cancers (Basel). 2019 Nov 27;11(12):1881. doi: 10.3390/cancers11121881.
Resistance to chemotherapy is a major clinical challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we provide evidence that Rho associated coiled-coil containing protein kinase 2 (ROCK2) maintains gemcitabine resistance in gemcitabine resistant pancreatic cancer cells (GR cells). Pharmacological inhibition or gene silencing of ROCK2 markedly sensitized GR cells to gemcitabine by suppressing the expression of zinc-finger-enhancer binding protein 1 (ZEB1). Mechanically, ROCK2-induced sp1 phosphorylation at Thr-453 enhanced the ability of sp1 binding to ZEB1 promoter regions in a p38-dependent manner. Moreover, transcriptional activation of ZEB1 facilitated GR cells to repair gemcitabine-mediated DNA damage via ATM/p-CHK1 signaling pathway. Our findings demonstrate the essential role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells and provide strong evidence for the clinical application of fasudil, a ROCK2 inhibitor, in gemcitabine-refractory PDAC.
化疗耐药是胰腺导管腺癌（PDAC）治疗中的一项重大临床挑战。在此，我们提供证据表明，含Rho相关卷曲螺旋蛋白激酶2（ROCK2）在吉西他滨耐药胰腺癌细胞（GR细胞）中维持吉西他滨耐药性。ROCK2的药理学抑制或基因沉默通过抑制锌指增强子结合蛋白1（ZEB1）的表达，使GR细胞对吉西他滨显著敏感。在机制上，ROCK2诱导的sp1在苏氨酸-453处磷酸化，以p38依赖的方式增强了sp1与ZEB1启动子区域结合的能力。此外，ZEB1的转录激活促进GR细胞通过ATM/p-CHK1信号通路修复吉西他滨介导的DNA损伤。我们的研究结果证明了ROCK2在胰腺癌细胞EMT诱导的吉西他滨耐药中的重要作用，并为ROCK2抑制剂法舒地尔在吉西他滨难治性PDAC中的临床应用提供了有力证据。
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