Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 12, Issue 6A, Pages 2334-2349Publisher
WILEY
DOI: 10.1111/j.1582-4934.2008.00257.x
Keywords
polo-like kinase 1; RNA interference; siRNA; gemcitabine; cell cycle; G2; M arrest apoptosis; pancreatic cancer
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Funding
- National Natural Science Foundation of China [39670265]
- China Postdoctoral Science Foundation [20060390294]
- Research Start-up Funds of Ministry of Education [2003-14]
- NATIONAL CANCER INSTITUTE [Z01BC010847, ZIABC010847] Funding Source: NIH RePORTER
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Gemcitabine is the first-line chemotherapeutic agent for advanced adenocarcinoma of the pancreas; however, chemoresistance to gemcitabine remains a major cause of failure for the clinical treatment of this disease. Polo-like kinase 1 (Plk-1) is highly expressed in pancreatic cancer cell lines and pancreatic tumour tissues, and is involved in a wide variety of cell cycle processes. Nevertheless, its biological role and implication for gemcitabine resistance are not clearly defined. In this study, we used RNA-interference (RNAi)-mediated depletion of Plk-1 to determine its potential for sensitizing pancreatic tumour cells to gemcitabine. We showed that the level of Plk-1 protein was correlated significantly with gemcitabine resistance in human pancreatic adenocarcinoma cells and that overexpression of Plk-1 reduced sensitivity to gemcitabine in these cells. In addition, small interfering RNA (siRNA)-mediated knockdown of Plk-1 caused cell cycle arrest at G2/M and the reduction of cellular proliferation. More importantly, the treatment of pancreatic cancer cells with Plk-1 siRNA followed by exposure to gemcitabine dramatically decreased cell viability and increased cellular apoptosis, as compared with treatment with either agent alone. These observations indicate that down-regulation of Plk-1 expression by RNAi enhances gemcitabine sensitivity and increases gemcitabine cytotoxicity in pancreatic tumour cells. This is the first demonstration that the combination of Plk-1 gene therapy and gemcitabine chemotherapy has synergistic anti-tumour activity against pancreatic carcinoma in vitro. This combination treatment warrants further investigation as an effective therapeutic regimen for patients with resistant pancreatic cancer and other tumours.
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