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

PAEZ, ALEJANDRA V; PALLAVICINI, CARLA; SCHUSTER, FEDERICO; VALACCO, MARIA PIA; GIUDICE, JIMENA; ORTIZ, EMILIANO G; ANSELMINO, NICOLÁS; LABANCA, ESTEFANIA; BINAGHI, MARIA; SALIERNO, MARCELO; MARTÍ, MARCELO A; COTIGNOLA, JAVIER H; WOLOSZYNSKA-READ, ANNA; BRUNO, LUCIANA; LEVI, VALERIA; NAVONE, NORA; VAZQUEZ, ELBA S; GUERON, GERALDINE

Cell Death and Disease

Nature PUBLISHING GROUP

Año: 2016 vol. 7

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.