Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells

Oncogene. 2001 Aug 16;20(36):4995-5004. doi: 10.1038/sj.onc.1204554.

Abstract

Inherent or acquired drug resistance is one of the major problems in chemotherapy. The mechanisms by which cancer cells survive and escape the cytotoxic effects of chemotherapeutic agents are essentially unknown. In the present study, we demonstrate that in the MDA-MB-231 and MDA-MB-435 breast cancer cells, ligation of beta1 integrins by their extracellular matrix ligands inhibits significantly apoptosis induced by paclitaxel and vincristine, two microtubule-directed chemotherapeutic agents that are widely used in the therapy of breast cancer. We show that beta1 integrin signaling inhibits drug-induced apoptosis by inhibiting the release of cytochrome c from the mitochondria in response to drug treatment. Further, integrin-mediated protection from drug-induced apoptosis and inhibition of cytochrome c release are dependent on the activation of the PI 3-kinase/Akt pathway. Our results identify beta1 integrin signaling as an important survival pathway in drug-induced apoptosis in breast cancer cells and suggest that activation of this pathway may contribute to the generation of drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Adhesion
  • Cytochrome c Group / metabolism
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Integrin beta1 / physiology*
  • Mitochondria / metabolism
  • Paclitaxel / pharmacology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Tumor Cells, Cultured
  • Vincristine / pharmacology

Substances

  • Antineoplastic Agents, Phytogenic
  • Cytochrome c Group
  • Integrin beta1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Vincristine
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Paclitaxel