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Oncotarget. 2016 Sep 6;7(36):57955-57969. doi: 10.18632/oncotarget.10799.

Ligand activated progesterone receptor B drives autophagy-senescence transition through a Beclin-1/Bcl-2 dependent mechanism in human breast cancer cells.

Author information

1
Centro Sanitario, University of Calabria, Rende, Italy.
2
Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy.
3
DiBEST University of Calabria, Rende, Italy.
4
Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.

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.

KEYWORDS:

Bcl-2; cell cycle arrest; p16; pRb; progesterone

PMID:
27462784
PMCID:
PMC5295403
DOI:
10.18632/oncotarget.10799
[Indexed for MEDLINE]
Free PMC Article

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