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Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
Open AccessArticle

DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

1
Francis Rodier Lab, Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de L’université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada
2
Fred Saad Lab, Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de L’université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada
3
Département de Chirurgie, Université de Montréal, Montreal, QC H3C 3J7, Canada
4
Département de Radiologie, Radio-Oncologie et Médecine Nucléaire, Université de Montréal, Montreal, QC H3T 1A4, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Cells 2020, 9(7), 1593; https://doi.org/10.3390/cells9071593 (registering DOI)
Received: 5 June 2020 / Revised: 24 June 2020 / Accepted: 26 June 2020 / Published: 1 July 2020
Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells. View Full-Text
Keywords: prostate cancer; cellular senescence; senolytics; PARP inhibitor; enzalutamide prostate cancer; cellular senescence; senolytics; PARP inhibitor; enzalutamide
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Malaquin, N.; Vancayseele, A.; Gilbert, S.; Antenor-Habazac, L.; Olivier, M.-A.; Ait Ali Brahem, Z.; Saad, F.; Delouya, G.; Rodier, F. DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity. Cells 2020, 9, 1593.

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