Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells

Cancer Lett. 2008 Mar 8;261(1):108-19. doi: 10.1016/j.canlet.2007.11.022. Epub 2008 Jan 2.

Abstract

The purpose of this study was to investigate the possible role of PI-3K/Akt2 pathway in docetaxel-induced apoptosis. Here we showed that transfection of full-length Akt2 into breast and ovarian cancer cells could provoke Akt phosphorylation and induce an enhanced resistance to docetaxel. FN adhesion promoted Akt phosphorylation in highly metastatic cancer cells A2780 and MDAMB231, and further brought on significant protection for tumor cells against docetaxel-induced apoptosis. Inhibition of Akt2 activity by co-transfection with two shRNA vectors targeting the same Akt2 mRNA or simply by administration with PI 3-Kinase inhibitor Ly294002 counteracted the ability of FN to protect cells from undergoing apoptosis induced by docetaxel. We further showed that Akt2 activation protected against docetaxel-induced apoptosis by regulating survivin levels in a PI 3-Kinase-dependent manner. We conclude that FN/PI-3K/Akt2 pathway might play an important role in inducing resistance to docetaxel in breast and ovarian cancer cells. Our results therefore indicate that the activation of Akt2, promoted by FN attachment, might be critical in determining whether cells survive or undergo apoptosis. Targeting the PI-3K/Akt2 pathway might be a promising strategy for enhancing sensitivity to docetaxel in breast or ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / metabolism*
  • Docetaxel
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Fibronectins / pharmacology*
  • Humans
  • Ovarian Neoplasms / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology*
  • Signal Transduction
  • Taxoids / pharmacology*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Fibronectins
  • Taxoids
  • Docetaxel
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt