Cross-talk between integrins and oncogenes modulates chemosensitivity

Mol Pharmacol. 2009 Apr;75(4):947-55. doi: 10.1124/mol.108.051649. Epub 2009 Jan 21.

Abstract

Chemotherapy often relies on cancer cell death resulting from DNA damage. The p53 tumor suppressor pathway that is an important player in DNA damage response is frequently inactivated in cancer. Genotoxicants also activate DNA damage-independent stress pathways and activity of oncogenic signaling and adhesive interactions with the cancer microenvironment can have a strong impact on chemosensitivity. Here, we have investigated how two different oncogenes modulate the response to genotoxicants in the context of two classes of integrin adhesion receptors. Epithelial cells expressing either beta1 or beta3 integrins, in which p53 activity is suppressed, undergo G(2) arrest but show little apoptosis after treatment with cisplatin or other genotoxicants. The apoptotic response is strongly enhanced by the c-Src[Y530F] oncogene in cells expressing beta1 integrins, whereas such sensitization is reduced when these cells are engineered to express beta3 integrins instead. The H-Ras[G12V] oncogene fails to sensitize, regardless of the integrin expression profile. The enhanced sensitivity induced by c-Src[Y530F] in the context of beta1 integrins does not rely on p53-mediated DNA damage signaling but instead involves increased endoplasmic reticulum stress and caspase-3 activation. Our data implicate that the expression profiles of oncogenes and integrins strongly affect the response to chemotherapeutics and may thus determine the efficacy of chemotherapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Chemoreceptor Cells / physiology*
  • Humans
  • Integrin beta Chains / physiology
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Integrins / deficiency
  • Integrins / genetics
  • Integrins / physiology*
  • Oncogenes / physiology*
  • Protein Binding / physiology
  • Receptor Cross-Talk / physiology*
  • Signal Transduction / physiology

Substances

  • Integrin beta Chains
  • Integrin beta1
  • Integrins