Prostate cancer is one of the most prevalent cancers among men and castration-resistant prostate cancer is the most clinically challenging form which an effective therapy is still lacking. Prostate cancer development and progression are strictly associated to inflammatory condition, indeed, several factors, including bacterial and viral agents, cause inflammations in the prostate gland that might culminate in inflammasome activation which leads to the activating cleavage of the inflammatory mediators IL-1β and IL-18. Their subsequent secretion in the microenvironment modulates cell function in an autocrine or paracrine manner. Prostate cancer cells can also affect the behavior of microenvironment receding cells via extracellular vesicles (EVs), important mediators of cell-cell communication. Several reports demonstrate that EVs exert an immunosuppressive action by affecting immune cells response. The prostate gland secretes a specific kind of EVs called prostasomes, which are physiologically involved in male fertility. However, the role of prostate cancer secreted EVs on the inflammatory crosstalk between cancer cells and their normal counterparts remains largely unknown. The aim of our study was to investigate whether EVs, release the from advanced stage prostate cancer cells PC3, could affect normal prostate cells (PNT2) behavior focusing on the IL-1β activation pathway. We first demonstrated that PC3 cells contain active NLRP3-inflammatory cascade and secret mature IL-1β, whereas non-cancerous PNT2 cells display lower levels of active caspase-1 and secret lower amounts of IL-1β. EVs purified from a PC3 culture medium were used to mimic prostate cancer microenvironment, where normal prostate PNT2 cells reside. PC3-EVs affect the inflammatory response of normal PNT2 cells inducing an LPS-independent caspase-1-mediated IL-1β maturation. We showed that caspase-1 activation by PC3-EVs depends on ERK1/2- mediated lysosomal destabilization and cathepsin B activation. Our results reveal that by inducing an inflammatory response on normal prostate cells, EVs might reinforce the tumor-promoting microenvironment
Inflammasome activation by prostate-cancer derived extracellular vesicles
Mezzasoma Letizia;Costanzi Egidia;Talesa Vincenzo Nicola;Bellezza Ilaria
2019
Abstract
Prostate cancer is one of the most prevalent cancers among men and castration-resistant prostate cancer is the most clinically challenging form which an effective therapy is still lacking. Prostate cancer development and progression are strictly associated to inflammatory condition, indeed, several factors, including bacterial and viral agents, cause inflammations in the prostate gland that might culminate in inflammasome activation which leads to the activating cleavage of the inflammatory mediators IL-1β and IL-18. Their subsequent secretion in the microenvironment modulates cell function in an autocrine or paracrine manner. Prostate cancer cells can also affect the behavior of microenvironment receding cells via extracellular vesicles (EVs), important mediators of cell-cell communication. Several reports demonstrate that EVs exert an immunosuppressive action by affecting immune cells response. The prostate gland secretes a specific kind of EVs called prostasomes, which are physiologically involved in male fertility. However, the role of prostate cancer secreted EVs on the inflammatory crosstalk between cancer cells and their normal counterparts remains largely unknown. The aim of our study was to investigate whether EVs, release the from advanced stage prostate cancer cells PC3, could affect normal prostate cells (PNT2) behavior focusing on the IL-1β activation pathway. We first demonstrated that PC3 cells contain active NLRP3-inflammatory cascade and secret mature IL-1β, whereas non-cancerous PNT2 cells display lower levels of active caspase-1 and secret lower amounts of IL-1β. EVs purified from a PC3 culture medium were used to mimic prostate cancer microenvironment, where normal prostate PNT2 cells reside. PC3-EVs affect the inflammatory response of normal PNT2 cells inducing an LPS-independent caspase-1-mediated IL-1β maturation. We showed that caspase-1 activation by PC3-EVs depends on ERK1/2- mediated lysosomal destabilization and cathepsin B activation. Our results reveal that by inducing an inflammatory response on normal prostate cells, EVs might reinforce the tumor-promoting microenvironmentI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.