IGFBP-3 sensitizes antiestrogen-resistant breast cancer cells through interaction with GRP78.
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.
Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, 23298, USA.
Chao
C
Li
Aki
A
Harada
Youngman
Y
Oh
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens; D005260:Female; D000077267:Fulvestrant; D015723:Gene Library; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D025941:Protein Interaction Mapping; D013629:Tamoxifen / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D018931:Antineoplastic Agents, Hormonal; D018076:DNA, Complementary; D000091342:Endoplasmic Reticulum Chaperone BiP; D020847:Estrogen Receptor Modulators; D004967:Estrogens; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009363:Neoplasm Proteins; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D053179:Caspase 7