Abstract
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.
Highlights
With a 5-year survival rate less than 5% [1], pancreatic ductal adenocarcinoma (PDAC) has the propensities of difficult diagnosis, early metastasis, and treatment-resistance [2]
According to the construction method of gemcitabine resistant pancreatic cancer (GR) cells, we speculated that the upregulation of Rho associated coiled-coil containing protein kinase 2 (ROCK2) in GR cells might be due to gemcitabine-induced stress or gemcitabine selection in parental cells
In order to explore whether ROCK2 was upregulated under gemcitabine selection, we compared the ROCK2 expression in parental cells and selected parental cells, which could stably grow in the medium with 5.0 μm gemcitabine
Summary
With a 5-year survival rate less than 5% [1], pancreatic ductal adenocarcinoma (PDAC) has the propensities of difficult diagnosis, early metastasis, and treatment-resistance [2]. Radical resection are not suitable for most patients, and chemotherapy remains the most frequent treatment option for advanced PDAC [3]. PDAC patients treated with chemotherapeutic drugs tend to develop chemotherapy resistance and lead to treatment failure [4,5]. Gemcitabine is not satisfactory as the first-line agent for pancreatic cancer due to the endogenous and exogenous drug resistance. The endogenous drug resistance mainly refers to the changes in drug metabolism, drug transport mechanism, and abnormal activation and inactivation of intracellular signaling pathways, while exogenous drug resistance is mainly caused by drug delivery hindrance [8,9]
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