CONICET | Buscador de Institutos y Recursos Humanos

Abstract: Prostate Cancer (PCa) is the second leading type of cancer in men. PCacells display abnormalities in their adhesive properties, which result in anaugmented capacity to resist chemotherapy and colonize other organs such asbone. Heme Oxygenase-1 (HO-1) acts as a cellular rheostat counteractingoxidative and inflammatory damage. We previously showed that HO-1 over-expression impairs tumor growth and angiogenesis in vivo. Given that inflammationis critical for the development and progression of PCa and that bone is the mostcommon homing organ for PCa metastases, we used a co-culture transwell systemfor tumoral and bone progenitor cells and quantified filopodia structures at theleading edge of PCa cells. Briefly, PC3 cells pre-treated or not with hemin (potentinducer of HO-1; 50uM, 24h) were co-cultured with the murine MC3T3 or RAW264.7 cells for 24h. Conditioned media (CMs) were collected and added to newPC3 cultures for 24h.Results show that the CM from PC3/MC3T3 or PC3/RAW264.7 co-cultures, have anegative impact both in the number of filopodia per cell and contacts among them.However, hemin pre-treatment of PC3 cells prior to co-culture, prevented thereduction in the number of filopodia and cell contacts.High-throughput secretomic analysis of CMs (nanoLC-MS/MS(Orbitrap) identifiedmore than 30 proteins differentially released, in the CMs, of note: cadherins,collagen and critical proteins associated to cell detachment. Interestingly, thebioinformatics screening for these cytoskeletal-related proteins showed asignificant misregulation in prostate adenocarcinoma compared to normal tissue.Altogether, our findings demonstrate that HO1 modulation in PCa cells in co-culture with bone progenitor cells induces the release of key cytoskeleton-regulating proteins that impact on cell morphology, favoring a less invasivephenotype towards homing organs.