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RNA interference-mediated silencing of the polo-like kinase 1 gene enhances chemosensitivity to gemcitabine in pancreatic adenocarcinoma cells.



Published on:2016-06-25   Views:180

Abstract

Gemcitabine is the first-line chemotherapeutic agent for advanced adenocarcinomaof the pancreas; however, chemoresistance to gemcitabine remains a major causeof failure for the clinical treatment of this disease. Polo-like kinase 1(Plk-1) is highly expressed in pancreatic cancer cell lines and pancreatictumour tissues, and is involved in a wide variety of cell cycle processes.Nevertheless, its biological role and implication for gemcitabine resistanceare not clearly defined. In this study, we used RNA-interference(RNAi)-mediated depletion of Plk-1 to determine its potential for sensitizingpancreatic tumour cells to gemcitabine. We showed that the level of Plk-1protein was correlated significantly with gemcitabine resistance in humanpancreatic adenocarcinoma cells and that overexpression of Plk-1 reducedsensitivity to gemcitabine in these cells. In addition, small interfering RNA(siRNA)-mediated knockdown of Plk-1 caused cell cycle arrest at G2/M and thereduction of cellular proliferation. More importantly, the treatment ofpancreatic cancer cells with Plk-1 siRNA followed by exposure to gemcitabinedramatically decreased cell viability and increased cellular apoptosis, ascompared with treatment with either agent alone. These observations indicatethat down-regulation of Plk-1 expression by RNAi enhances gemcitabinesensitivity and increases gemcitabine cytotoxicity in pancreatic tumour cells.This is the first demonstration that the combination of Plk-1 gene therapy andgemcitabine chemotherapy has synergistic anti-tumour activity againstpancreatic carcinoma in vitro. This combination treatment warrants furtherinvestigation as an effective therapeutic regimen for patients with resistantpancreatic cancer and other tumours.<span lang="EN-US" style=""color:black;">