Suppressed tumour growth and enhanced chemosensitivity by RNA interference targeting Aurora-A in the PC3 human prostate cancer model

BJU Int. 2010 Jul;106(1):121-7. doi: 10.1111/j.1464-410X.2009.09047.x. Epub 2009 Nov 12.

Abstract

Objectives: To investigate the inhibitory effects of Aurora-A expression in prostate cancer cells on their growth and chemosensitivity.

Patients and methods: Aurora-A expression in radical prostatectomy specimens obtained from 193 patients were evaluated by immunohistochemical staining. We then established PC3 cells in which the expression vector containing short-hairpin RNA (shRNA) targeting Aurora-A was introduced (PC3/sh-A). The growth and the sensitivity to docetaxel in PC3/sh-A were compared with those in PC3 transfected with control vector alone (PC3/C).

Results: Immunohistochemistry showed that there were various levels of Aurora-A expression in most prostate cancer tissues, and the expression levels of Aurora-A in prostate cancer were significantly related to Gleason score. Expression levels of both Aurora-A mRNA and protein in PC3/sh-A were approximately 20% of those in PC3/C. In vitro growth of PC3/sh-A was significantly worse than that of PC3/C, and the proportion of PC3/sh-A in the G2-M phase was significantly greater than that of PC3/C. The 50% inhibitory concentration of docetaxel in PC3/sh-A decreased by 67% compared with that in PC3/C. Tumour volume in nude mice injected with PC3/sh-A was significantly smaller than that with PC3/C. Furthermore, treatment of nude mice bearing PC3/sh-A tumour with docetaxel (10 mg/kg, once weekly for 4 weeks) achieved a synergistic cytotoxic effect, despite the lack of an enhanced antitumour effect of docetaxel on PC3/C tumours.

Conclusions: The suppression of Aurora-A using shRNA could be a useful therapeutic strategy against androgen-independent prostate cancer, through growth inhibition as well as enhanced chemosensitivity.

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Aurora Kinase A
  • Aurora Kinases
  • Docetaxel
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference*
  • Taxoids / pharmacology*
  • Tumor Burden
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Taxoids
  • Docetaxel
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases