Heme Oxygenase -1 (HO-1) in the forefront of a multi-molecular network that governs cell-cell contacts and filopodia-induced zippering in prostate cancer

PAEZ ALEJANDRA; PALLAVICINI, CARLA; SCHUSTER, FEDERICO; VALACCO, PIA; GIUDICE, JIMENA; ORTIZ, EMILIANO GERMÁN; ANSELMINO, NICOLÁS; LABANCA, ESTEFANIA; SALIERNO MARCELO; BINAGHI, MARIA; MARTI MARCELO; COTIGNOLA, JAVIER HERNÁN; LEVI, VALERIA; BRUNO, LUCIANA; WOLOSZYNSKA-READ, ANNA; GUERON, GERALDINE; VAZQUEZ, ELBA SUSANA; NAVONE, NORA

Mar del Plata

Congreso; LXI Reunión Científica anual de la Sociedad Argentina de la Investigación Clínica. SAIC; 2016

SAIC

Prostate Cancer (PCa) cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown that heme-oxygenase 1 (HO-1) is implicated in cell morphology regulation in PCa. Here, through a multi ?omics? approach we define the HO-1 interactome in PCa, identifying HO-1 molecular partners associated with the integrity of the cellular cytoskeleton. The bioinformatics screening for these cytoskeletal-related partners reveal that they are highly misregulated in prostate adenocarcinoma compared to normal prostate tissue. Under HO-1 induction, PCa cells present reduced frequency in migration events, trajectory and cell velocity and, a significant higher proportion of filopodia-like protrusions among neighboring cells. Moreover forced-expression of HO-1 was also capable of altering cell protrusions in transwell co-culture systems of PCa cells with MC3T3 cells (pre-osteoblastic cell line). Accordingly, these effects were reversed under siHO. Transcriptomics profiling evidenced significant modulation of key markers related to cell adhesion and cell-cell communication under HO-1 induction. The integration from our omics-based research provides a four molecular pathway foundation (ANXA2/HMGA1/POU3F1; NFRSF13/GSN; TMOD3/RAI14/VWF; PLAT/PLAU) behind HO-1 regulation of tumor cytoskeletal cell compartments. The complementary proteomics and transcriptomics approaches presented here promise to move us closer to unravel the molecular framework underpinning HO-1 involvement in the modulation of cytoskeleton pathways, pushing towards a less aggressive phenotype, showcasing its relevance as a key homeostatic factor against the aggressive disease.