title: RNA interference-mediated silencing of the polo-like kinase 1 gene enhances chemosensitivity to gemcitabine in pancreatic adenocarcinoma cells.
abstract: 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.
authors.affiliation: Department of Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Sun
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: You
authors.forename: J L
authors.initials: JL
authors.lastname: Jacobs
authors.forename: K
authors.initials: K
authors.lastname: Gardner
authors.forename: D
authors.initials: D
authors.lastname: Yuan
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.forename: Q
authors.initials: Q
authors.lastname: Du
authors.forename: C
authors.initials: C
authors.lastname: Dai
authors.forename: Z
authors.initials: Z
authors.lastname: Qian
authors.forename: K
authors.initials: K
authors.lastname: Jiang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: Q Q
authors.initials: QQ
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D003841:Deoxycytidine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000093542:Gemcitabine; D000097869:Polo-Like Kinase 1