title: Plumbagin sensitizes breast cancer cells to tamoxifen-induced cell death through GRP78 inhibition and Bik upregulation.
abstract: The glucose regulated protein 78 (GRP78) is a major chaperone of the endoplasmic reticulum, and a prosurvival component of the unfolded protein response. GRP78 is upregulated in many types of cancers, including breast cancer. Research has suggested that GRP78 overexpression confers chemoresistance to anti-estrogen agents through a mechanism involving the inhibition of a pro-apoptotic BH3-only protein, Bik. In the present research the role of plumbagin, a naturally occurring naphthoquinone, in GRP78-associated cell death inhibition was examined. The results demonstrated that plumbagin inhibits GRP78 activity and GRP78 inhibition contributes to plumbagin-mediated cell death induction. Furthermore, Bik upregulation was associated with plumbagin-induced cell death and an increase in plumbagin-mediated Bik induction was observed upon GRP78 downregulation. Plumbagin sensitized estrogen-positive breast cancer cells to tamoxifen and the association of GRP78 inhibition and Bik upregulation in plumbagin-mediated cell sensitization was shown. Collectively, the results of this research suggest that plumbagin inhibits the antiapoptotic activity of GRP78 leading to Bik upregulation and apoptosis induction, which contributes to the sensitization of breast cancer cells to tamoxifen.
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, Gdansk, 80-307, Poland.|Department of Human Physiology, Faculty of Health Sciences with Subfaculty of Nursing, Medical University of Gdansk, Tuwima 15, Gdansk, 80-210, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kawiak
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, Gdansk, 80-307, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Domachowska
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, Gdansk, 80-307, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jaworska
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, Gdansk, 80-307, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Lojkowska
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009285:Naphthoquinones / Q000494:pharmacology*; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009285:Naphthoquinones; D013629:Tamoxifen; C014758:plumbagin