Analysis of senescence-associated secretory phenotype induced by different androgen receptor ligands in human prostate cancer cells

Androgen receptor (AR) is a major drug target in prostate cancer (PCa) therapy. Both supraphysiological androgen level (SAL) and clinically used AR antagonist Enzalutamide (ENZ) inhibit PCa cell proliferation by inducing cellular senescence, an irreversible cell cycle arrest, which seems to be a potential strategy for PCa therapy. Unfortunately, senescent cells are known to secrete cytokines termed as senescence-associated secretory phenotype (SASP) which may affect tumor microenvironment and neighboring cells. Effects of SASP depend on the secreted factors. This thesis shows that the composition of SASP secretome is different between SAL- and ENZ-treated human PCa cells. Moreover, the SASP of SAL-treated cells functionally suppresses, but the SASP of ENZ-treated cells promotes PCa cell proliferation. However, further results show that SASP of either SAL- or ENZ-treated cells suppresses lymphocyte proliferation, whereas AR ligand-treated PCa cells themselves are resistant to lymphocyte-mediated apoptosis. Such immune-suppressive effects may provide long-term disadvantages for PCa therapy. Thus, potential senolytic compounds to eliminate AR ligand-induced cellular senescent cells were analyzed. This thesis identifies activated AKT signaling as an underlying mechanism for apoptotic resistance of both SAL- and ENZ-treated cells, but through distinct downstream signals. This difference strikingly leads to distinct apoptotic sensitivity towards specific senolytic compounds; ENZ-treated cells towards AKT inhibitor and SAL-treated cells towards HSP90 inhibitor. These novel findings suggest that treatment with suitable senolytic compound after particular AR ligand-induced cellular senescence might be useful therapeutic strategy in PCa therapy. Taken together, this is the first study highlighting side-effects mediated by AR ligand-induced cellular senescence via SASP and also demonstrating a potential strategy to eliminate AR ligand-treated cells with senolytic compounds.