title: Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells.
abstract: Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.
authors.affiliation: Discipline of Oncology, Department of Radiology and Oncology, Faculty of Medicine, University of São Paulo, CEP 01246-903, São Paulo, Brazil.
authors.forename: Michelly C
authors.initials: MC
authors.lastname: Pereira
authors.forename: Simone A
authors.initials: SA
authors.lastname: de Bessa-Garcia
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Pavanelli
authors.forename: Lourival
authors.initials: L
authors.lastname: Antunes
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
authors.forename: Maria A
authors.initials: MA
authors.lastname: Nagai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D043823:Taxoids / Q000494:pharmacology; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D043823:Taxoids; C101296:prostate apoptosis response-4 protein; D000077143:Docetaxel