title: Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells.
abstract: Loss of progesterone-receptors (PR) expression is associated with breast cancer progression. Herein we provide evidence that OHPg/PR-B through Beclin-1 evoke autophagy-senescence transition, in breast cancer cells. Specifically, OHPg increases Beclin-1 expression through a transcriptional mechanism due to the occupancy of Beclin-1 promoter by PR-B, together with the transcriptional coactivator SRC-2. This complex binds at a canonical half progesterone responsive element, which is fundamental for OHPg effects, as shown by site-directed mutagenesis. Beside, OHPg via non-genomic action rapidly activates JNK, which phosphorylates Bcl-2, producing the functional release from Beclin-1 interaction. This is not linked to an efficient autophagic flux, since p62 levels, marker of degradation via lysosomes, were not reduced after sustained OHPg stimulus. Instead, the cell cycle inhibitor p27 was induced, together with an irreversible G1 arrest, hallmark of cellular senescence. Specifically the increase of senescence-associated β-galactosidase activity was blocked by Bcl-2 siRNA but also by Beclin-1 siRNA. Collectively these findings support the importance of PR-B expression in breast cancer cells, thus targeting PR-B may be a useful strategy to provide additional approaches to existing therapies for breast cancer patients.
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Amicis
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Guido
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giordano
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Donà
authors.affiliation: Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Rizza
authors.affiliation: Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: DiBEST University of Calabria, Rende, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Perrotta
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Sisci
authors.affiliation: Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Panno
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Tramontano
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Saveria
authors.initials: S
authors.lastname: Aquila
authors.affiliation: Centro Sanitario, University of Calabria, Rende, Italy.|Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C000595707:BCL2 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D014157:Transcription Factors; C097314:progesterone receptor B; D011374:Progesterone; D001616:beta-Galactosidase
keywords: Bcl-2; cell cycle arrest; p16; pRb; progesterone