Journal Article

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

Antenor-Habazac, Laureen, Vancayseele, Arthur, Saad, Fred, Ait Ali Brahem, Zakia, Gilbert, Sophie, Olivier, Marc-Alexandre, Malaquin, Nicolas, Delouya, Guila, Rodier, Francis

2020

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Antineoplastic Agents - pharmacology / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Apoptosis / Bcl-2 protein / Bcl-x protein / Cancer therapies / Cell Cycle - drug effects / Cell death / Cell Death - drug effects / Cell fate / Cell Line, Tumor / Cell Proliferation - drug effects / Cell therapy / cellular senescence / Cellular Senescence - drug effects / Deoxyribonucleic acid / DNA / DNA damage / DNA Damage - drug effects / DNA Damage - radiation effects / enzalutamide / Humans / Male / Mutation / Ovarian cancer / p53 Protein / PARP inhibitor / Phenotypes / Phenylthiohydantoin - analogs & derivatives / Phenylthiohydantoin - pharmacology / Phthalazines - pharmacology / Piperazines - pharmacology / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - metabolism / Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors / Radiation / Ribose / Senescence / senolytics / Tumor suppression