CONICET | Buscador de Institutos y Recursos Humanos

Prostate cancer is the most common cancer in males. The second?generation anti?androgens, such as Enzalutamide, have been used to treat advanced prostate cancer leading to improvement patient lifespan.Aberrant Notch signaling has been widely demonstrated to be associated with tumor progression and therapeutic resistance in many types of cancers. However, the role in prostate cancer is poorly understood.In this work, we aimed to study the role of Notch pathway in the development of prostate cancer and its regulation under Enzalutamide treatment.We first determined the expression of Notch1 and Notch4 receptors and the proliferation marker PCNA by IHQ in prostate tumor samples obtained by surgery.In prostate cancer PC3 cells under Notch pathway inhibition with DAPT, the expression of TMPRSS2, an androgen dependent gene, showed lower levels after 24 h of treatment (10 y 30 µM) by RT-qPCR (n=2; p=0.02). In addition, we observed by WB a trend of reduction in PCNA expression with DAPT (30 µM) after 24 and 48 h (n=3). In turn, Enzalutamide treatment (30 y 50 µM) reduced the levels of HES1, a target gene of the Notch pathway, determined by RT- qPCR (n=3).Cell viability was measured using MTS assay and we observed significantly reduced viability of prostate cancer PC3 cells both with DAPT (p=0.0027; n=3) and with Enzalutamide isolated treatment (p=0.0018; n=3). Importantly, the combined treatment with DAPT (10 µM) and Enzalutamide (50 µM) significantly reduced PC3 viability at 48 and 72 h (p=0.0043; n=3).Our results show Notch signaling activation in prostate PC3 cells and prostate tumor samples. Interestingly, DAPT treatment decreased the levels of TMPRSS2, and Enzalutamide decreased the levels of HES1. Moreover, we observed a significantly reduced viability both with DAPT and Enzalutamide isolated treatment and with the combined treatment. Our results suggest an interconnection between Notch and Androgen receptor pathways in prostate cancer.

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