Oncotarget

Research Papers:

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

Francesca De Amicis _, Carmela Guido, Marta Santoro, Francesca Giordano, Ada Donà, Pietro Rizza, Michele Pellegrino, Ida Perrotta, Daniela Bonofiglio, Diego Sisci, Maria Luisa Panno, Donatella Tramontano, Saveria Aquila and Sebastiano Andò

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Oncotarget. 2016; 7:57955-57969. https://doi.org/10.18632/oncotarget.10799

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Abstract

Francesca De Amicis1,2, Carmela Guido1,2, Marta Santoro1, Francesca Giordano2, Ada Donà1,2, Pietro Rizza2, Michele Pellegrino2, Ida Perrotta3, Daniela Bonofiglio1,2, Diego Sisci1,2, Maria Luisa Panno2, Donatella Tramontano4, Saveria Aquila1,2,*, Sebastiano Andò1,2,*

1Centro Sanitario, University of Calabria, Rende, Italy

2Department of Pharmacy, Health Science and Nutrition, University of Calabria, Rende, Italy

3DiBEST University of Calabria, Rende, Italy

4Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy

*Joint senior authors

Correspondence to:

Francesca De Amicis, email: [email protected]

Sebastiano Andò, email: [email protected]

Keywords: progesterone, Bcl-2, cell cycle arrest, pRb, p16

Received: February 03, 2016     Accepted: July 09, 2016     Published: July 23, 2016

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.


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