IGFBP-3 sensitizes antiestrogen-resistant breast cancer cells through interaction with GRP78

Cancer Lett. 2012 Dec 28;325(2):200-6. doi: 10.1016/j.canlet.2012.07.004. Epub 2012 Jul 16.

Abstract

IGFBP-3 is known to possess intrinsic biological activities such as anti-tumor property in addition to its IGF/IGF-R axis-dependent actions in a variety of human cancers including breast cancer. To investigate the molecular mechanisms underlying the intrinsic biological actions of IGFBP-3 on breast cancer cells, we performed yeast two-hybrid screening and found GRP78, known to cause drug-resistance, as a binding partner of IGFBP-3. Overexpression of IGFBP-3 in antiestrogen-resistant LCC9 cells showed that IGFBP-3 interacted with GRP78, resulting in disruption of the GRP78-caspase-7 complex, thereby activating caspase-7, and further inducing apoptosis. Combination of overexpression of IGFBP-3 and application of siRNAs against GRP78 led to decrease in cell viability upon ICI 182,780 treatment. These data suggest that IGFBP-3 could sensitize antiestrogen-resistant breast cancer cells to ICI 182,780 by preventing the anti-apoptotic function of GRP78.

Publication types

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

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caspase 7 / metabolism
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • DNA, Complementary / genetics
  • Drug Resistance, Neoplasm*
  • Endoplasmic Reticulum Chaperone BiP
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Receptor Modulators / pharmacology*
  • Estrogens
  • Female
  • Fulvestrant
  • Gene Library
  • Heat-Shock Proteins / physiology*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / physiology*
  • Neoplasm Proteins / physiology*
  • Neoplasms, Hormone-Dependent / metabolism
  • Neoplasms, Hormone-Dependent / pathology
  • Protein Interaction Mapping
  • Tamoxifen / pharmacology
  • Two-Hybrid System Techniques

Substances

  • Antineoplastic Agents, Hormonal
  • DNA, Complementary
  • Endoplasmic Reticulum Chaperone BiP
  • Estrogen Receptor Modulators
  • Estrogens
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Neoplasm Proteins
  • Tamoxifen
  • Fulvestrant
  • Estradiol
  • Caspase 7