NOTCH AND ANDROGEN RECEPTOR INVOLVEMENT IN PROSTATE CANCER DEVELOPMENT

AGUSTINA CHIMENTO; NADIA BONADEO; SOFÍA PERRONE; MARÍA LUCÍA ROMANO; ANA LAURA FONTANAZZA; AMILCAR OSORIO; ELENA CASCO; KURT VILLALBA; LICINA TESONE; MARÍA FERNANDA PARENTI; CAROLINA CRISTINA

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias 2022; 2022

Prostate cancer (PCa) remains among the leading causes of cancer-related deaths in men. Standard therapies for castration resistant prostate cancer (CRPC) include second-generation anti-androgens, such as Enzalutamide (Enz), which prolong patient lifespan. There is strong evidence that involves Notch pathway in prostate development but its role in PCa generation and progression is poorly understood.In this work, we aimed to study the Notch system association with prostate tumor development and resistance to treatment with Enzalutamide.In prostate cancer PC3 cells, we demonstrated AR expression by RT-qPRC. Instead, PSA expression was absent when evaluated culture cell supernantants by chemiluminescence. We injected subcutaneously Nude mice with PC3 cells and we observed an increased mRNA levels of Notch-1, a target gene of the Notch pathway Hes-1 and TMPRSS, an androgen dependent gene, in larger volume tumors compared to small tumors; mRNA levels of AR didn’t show differences. Moreover, under Notch pathway inhibition with DAPT, the expression of TMPRSS2, showed lower levels after 24 h of treatment (10 and 30 µM) by RT-qPCR (p=0.02;n=2). In turn, Enz treatment (30 and 50 µM) reduced the levels of HES1 determined by RT-qPCR (n=3). We observed significantly reduced viability, using MTS assay, of PC3 cells both with DAPT (p=0.0027;n=3) and Enz isolated treatments (p=0.0018;n=3), also with the combined treatment (p=0.0043;n=3). We observed reduced migratory abilities both with DAPT (p=0,0022;n=3) and Enz isolated treatment (p=ns; n=1.2), and also with the combined treatment (p=0,0526; n=3) using wound healing assay.  Our study shows in vitro and in vivo activation of the Notch pathway in PC3 cells, which would be involved in cell proliferation and migration. Importantly, our results suggest an interconnection between Notch and AR pathways in PCa. A combined approach with inhibitors of both pathways could be more effective, especially in patients with aggressive PCa.