Heme oxygenase-1 in the forefront Q1 of a multi-molecular network that governs cell?cell contacts and filopodia-induced zippering in prostate cancer

ALEJANDRA PAEZ; CARLA PALLAVICINI; FEDERICO SCHUSTER, MARIA PIA VALACCO1; JIMENA GIUDICE; EMILIANO ORTIZ1, NICOLÁS ANSELMINO1; ESTEFANIA LABANCA; MARIA BINAGHI, MARCELO SALIERNO, MARCELO MARTÍ, JAVIER COTIGNOLA; ANNA WOLOSZYNSKA-READ; LUCIANA BRUNO2,; VALERIA LEVI; NORA NAVONE; ELBA VAZQUEZ AND GERALDINE GUERON

CELL DEATH AND DIFFERENTIATION

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2016

1350-9047

Prostate cancer (PCa) cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resistchemotherapy and colonize distant organs. We have previously shown that heme oxygenase 1 (HO-1) is implicated in cellmorphology regulation in PCa. Here, through a multi ´omics´ approach we define the HO-1 interactome in PCa, identifying HO-1molecular partners associated with the integrity of the cellular cytoskeleton. The bioinformatics screening for these cytoskeletalrelatedpartners reveal that they are highly misregulated in prostate adenocarcinoma compared with normal prostate tissue. UnderHO-1 induction, PCa cells present reduced frequency in migration events, trajectory and cell velocity and, a significant higherproportion of filopodia-like protrusions favoring zippering among neighboring cells. Moreover forced expression of HO-1 was alsocapable 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 markersrelated to cell adhesion and cell?cell communication under HO-1 induction. The integration from our omics-based researchprovides a four molecular pathway foundation (ANXA2/HMGA1/POU3F1; NFRSF13/GSN; TMOD3/RAI14/VWF; and PLAT/PLAU)behind HO-1 regulation of tumor cytoskeletal cell compartments. The complementary proteomics and transcriptomics approachespresented here promise to move us closer to unravel the molecular framework underpinning HO-1 involvement in the modulationof cytoskeleton pathways, pushing toward a less aggressive phenotype in PCa