title: GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis.
abstract: The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor-positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation-induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation-induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance.
authors: Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
authors: Yong
authors: Y
authors: Fu
authors: Jianze
authors: J
authors: Li
authors: Amy S
authors: AS
authors: Lee
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004967:Estrogens / Q000172:deficiency*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C096820:BIK protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D004967:Estrogens; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein