Polo-like kinase 1 as predictive marker and therapeutic target for radiotherapy in rectal cancer

Am J Pathol. 2010 Aug;177(2):918-29. doi: 10.2353/ajpath.2010.100040. Epub 2010 Jun 25.

Abstract

The ability to predict tumor sensitivity toward radiotherapy may significantly impact the selection of patients for preoperative combined-modality therapy. The aim of the present study was to test the predictive value of Polo-like kinase 1 (PLK1) in rectal cancer patients and to investigate whether PLK1 plays a direct role in mediating radiation sensitivity. PLK1 expression was evaluated by immunohistochemistry (n = 76) or Affymetrix HG133 microarray (n = 20) on pretreatment biopsies of patients with advanced rectal cancer. Expression was correlated with both tumor regression in the resected specimen and long-term clinical outcome. Furthermore, we used small interfering RNAs (siRNAs) to down-regulate PLK1 expression in colorectal cancer cells and analyzed the effects of PLK1-specific siRNAs by Western blot and quantitative real-time PCR analysis, FACScan analysis, caspase 3/7 assays, and colony-forming assays. We observed that increased PLK1 protein expression was significantly related to a poorer tumor regression and a higher risk of local recurrence in uni- and multivariate analysis. A significant decrease of PLK1 expression by siRNAs in combination with ionizing radiation induced an increased percentage of apoptotic cells and increased caspase 3/7 activity. Furthermore, enhanced G(2)-M levels, decreased cellular viability, and reduced clonogenic survival were demonstrated, indicating a radiosensitizing effect of PLK1 depletion. Therefore, PLK1 may be a novel predictive marker for radiation response as well as a promising therapeutic target in rectal cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Humans
  • Microarray Analysis
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / therapeutic use
  • Radiation Tolerance / physiology*
  • Rectal Neoplasms* / drug therapy
  • Rectal Neoplasms* / metabolism
  • Rectal Neoplasms* / radiotherapy

Substances

  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1