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.

A Fine-Needle Aspirate–Based Vulnerability Assay Identifies Polo-Like Kinase 1 as a Mediator of Gemcitabine Resistance in Pancreatic Cancer

“…A separate analysis found Plk1 mRNA and protein to be overexpressed in clinical pancreatic cancer samples and in cell lines but more importantly decreasing Plk1-induced growth arrest in preclinical models (14). Yu et al showed recently that treatment of pancreatic cancer cells with Plk1 siRNA followed by exposure to gemcitabine dramatically decreased cell viability and increased cellular apoptosis compared with treatment with either agent alone (19).…”

Targeting Polo-Like Kinase 1 Enhances Radiation Efficacy for Head-and-Neck Squamous Cell Carcinoma

“…Recently, a nonadenosine triphosphate competitive (18) and an adenosine triphosphate-competitive inhibitor (19) have both progressed into Phase I clinical testing. Other groups have successfully knocked down Plk1 using small interfering ribonucleic acids (siRNAs), resulting in decreased in vitro growth of bladder (20) and prostate cancer cells (21), as well as increased chemosensitivity in pancreatic cancers (22). To date, no one has investigated such an approach for head-and-neck squamous cell carcinoma (HNSCC).…”

Side population in the pancreatic cancer cell lines SW1990 and CFPAC-1 is enriched with cancer stem-like cells

“…Our previous research showed that silencing of the PLK-1 gene can enhance chemosensitivity to gemcitabine in pancreatic adenocarcinoma cells (34). Notably, we found that the mRNA level of PLK-1 was also increased in SP cells.…”