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Conference Paper: The unfolded protein response regulator GRP78 as a novel target of BRCA1 for inhibiting stress-induced apoptosis

TitleThe unfolded protein response regulator GRP78 as a novel target of BRCA1 for inhibiting stress-induced apoptosis
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research
Citation
The 99th American Association of Cancer Research Annual Meeting (AACR), San Diego, CA, 12-16 April 2008. In Cancer Research, 2008, v. 68 n. 9, Abstract no. 1785 How to Cite?
AbstractThe tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We previously identified glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), with altered expression in ovarian surface epithelial cells derived from women with a family history of ovarian and/or breast cancer compared to those without such history. We report here that GRP78 is a novel downstream target of BRCA1. We showed that reconstitution of BRCA1-deficient cells with wild-type BRCA1 repressed GRP78 expression, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with BRCA1 inactivation, overexpression of GRP78 increased proliferation and decreased apoptosis in MCF-7 (breast carcinoma) and OVCAR-3 (ovarian carcinoma) cells. GRP78 overexpression also protected cells from endoplasmic reticulum (ER) stress- and chemotherapeutic drug-induced apoptosis. Knocking down GRP78 by siRNA sensitized these cells to stress-induced apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated tumor cell survival. These results reveal a novel mechanism for regulating GRP78 and suggest that enhancing UPR/ER stress response may be an important component of the BRCA1-associated tumorigenesis and chemoresistance. (This work is supported by Hong Kong Research Grants Council Grants HKU7484/04M to A.S.T.W.).
Persistent Identifierhttp://hdl.handle.net/10722/114863
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorKwan, WYen_HK
dc.contributor.authorYeung, HYen_HK
dc.contributor.authorWong, ASTen_HK
dc.contributor.authorHe, Qen_HK
dc.contributor.authorLee, ASen_HK
dc.contributor.authorLiu, Jen_HK
dc.date.accessioned2010-09-26T05:19:20Z-
dc.date.available2010-09-26T05:19:20Z-
dc.date.issued2008en_HK
dc.identifier.citationThe 99th American Association of Cancer Research Annual Meeting (AACR), San Diego, CA, 12-16 April 2008. In Cancer Research, 2008, v. 68 n. 9, Abstract no. 1785-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/114863-
dc.description.abstractThe tumor suppressor BRCA1 is mutated in a high percentage of familial breast and ovarian cancer, but our understanding of its mechanisms of action remains incomplete. We previously identified glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), with altered expression in ovarian surface epithelial cells derived from women with a family history of ovarian and/or breast cancer compared to those without such history. We report here that GRP78 is a novel downstream target of BRCA1. We showed that reconstitution of BRCA1-deficient cells with wild-type BRCA1 repressed GRP78 expression, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small interfering RNA (siRNA) enhanced GRP78 expression. Knockdown of BRCA1 also led to induction of other components of UPR, such as GRP94 and CHOP. Consistent with BRCA1 inactivation, overexpression of GRP78 increased proliferation and decreased apoptosis in MCF-7 (breast carcinoma) and OVCAR-3 (ovarian carcinoma) cells. GRP78 overexpression also protected cells from endoplasmic reticulum (ER) stress- and chemotherapeutic drug-induced apoptosis. Knocking down GRP78 by siRNA sensitized these cells to stress-induced apoptosis. This effect was reduced when the expression of BRCA1 was simultaneously knockdown by siRNA, indicating that BRCA1 also negatively regulates GRP78-mediated tumor cell survival. These results reveal a novel mechanism for regulating GRP78 and suggest that enhancing UPR/ER stress response may be an important component of the BRCA1-associated tumorigenesis and chemoresistance. (This work is supported by Hong Kong Research Grants Council Grants HKU7484/04M to A.S.T.W.).-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Researchen_HK
dc.titleThe unfolded protein response regulator GRP78 as a novel target of BRCA1 for inhibiting stress-induced apoptosisen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailYeung, HY: bhyyeung@gmail.comen_HK
dc.identifier.emailHe, Q: qyhe@hkucc.hku.hken_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.identifier.hkuros144162en_HK

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