This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fu, Y. Articles by Lee, A. S. Search for Related Content PubMed PubMed Citation Articles by Fu, Y. Articles by Lee, A. S.

GRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation–Induced Apoptosis

Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California

Requests for reprints: Amy S. Lee, Department of Biochemistry and Molecular Biology and the USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176. Phone: 323-865-0507; Fax: 323-865-0094; E-mail: amylee{at}usc.edu.

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. [Cancer Res 2007;67(8):3734–40]

This article has been cited by other articles:

				D. Xu, R. E. Perez, M. H. Rezaiekhaligh, M. Bourdi, and W. E. Truog Knockdown of ERp57 increases BiP/GRP78 induction and protects against hyperoxia and tunicamycin-induced apoptosis Am J Physiol Lung Cell Mol Physiol, July 1, 2009; 297(1): L44 - L51. [Abstract] [Full Text] [PDF]

				U. K. Misra, Y. Mowery, S. Kaczowka, and S. V. Pizzo Ligation of cancer cell surface GRP78 with antibodies directed against its COOH-terminal domain up-regulates p53 activity and promotes apoptosis Mol. Cancer Ther., May 1, 2009; 8(5): 1350 - 1362. [Abstract] [Full Text] [PDF]

				P. Baumeister, D. Dong, Y. Fu, and A. S. Lee Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis Mol. Cancer Ther., May 1, 2009; 8(5): 1086 - 1094. [Abstract] [Full Text] [PDF]

				Y. Fu, S. Wey, M. Wang, R. Ye, C.-P. Liao, P. Roy-Burman, and A. S. Lee Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium PNAS, December 9, 2008; 105(49): 19444 - 19449. [Abstract] [Full Text] [PDF]

				T. Racek, S. Buhlmann, F. Rust, S. Knoll, V. Alla, and B. M. Putzer Transcriptional Repression of the Prosurvival Endoplasmic Reticulum Chaperone GRP78/BIP by E2F1 J. Biol. Chem., December 5, 2008; 283(49): 34305 - 34314. [Abstract] [Full Text] [PDF]

				Y. A. Mebratu, B. F. Dickey, C. Evans, and Y. Tesfaigzi The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFN{gamma}-induced cell death J. Cell Biol., November 3, 2008; 183(3): 429 - 439. [Abstract] [Full Text] [PDF]

				J. J. Virrey, D. Dong, C. Stiles, J. B. Patterson, L. Pen, M. Ni, A. H. Schonthal, T. C. Chen, F. M. Hofman, and A. S. Lee Stress Chaperone GRP78/BiP Confers Chemoresistance to Tumor-Associated Endothelial Cells Mol. Cancer Res., August 1, 2008; 6(8): 1268 - 1275. [Abstract] [Full Text] [PDF]

				D. Dong, M. Ni, J. Li, S. Xiong, W. Ye, J. J. Virrey, C. Mao, R. Ye, M. Wang, L. Pen, et al. Critical Role of the Stress Chaperone GRP78/BiP in Tumor Proliferation, Survival, and Tumor Angiogenesis in Transgene-Induced Mammary Tumor Development Cancer Res., January 15, 2008; 68(2): 498 - 505. [Abstract] [Full Text] [PDF]

				H. K. Lee, C. Xiang, S. Cazacu, S. Finniss, G. Kazimirsky, N. Lemke, N. L. Lehman, S. A. Rempel, T. Mikkelsen, and C. Brodie GRP78 is overexpressed in glioblastomas and regulates glioma cell growth and apoptosis Neuro-oncol, January 1, 2008; 10(3): 236 - 243. [Abstract] [Full Text] [PDF]