HO-1 GOVERNS THE CYTOSKELETON AT FILOPODIA: PULLING THE BRAKES ON THE MIGRATORY CAPACITY OF PROSTATE TUMORAL CELLS

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

Praga

Conferencia; 9th Internationa Conference on HemeOxygenase 1; 2016

Congress Prague

Prostate Cancer (PCa) is the second leading cause of cancer in men. The misregulation of the expression of cytoskeletal proteins plays an important role in cancer, augmenting the capacity to colonize distant organs and metastasize, as well as conferring resistance to chemotherapy. We have previously showed that heme-oxygenase 1 (HO-1) has a strong anti-tumoral effect in PCa. High-throughput proteomic platforms are now identifying and quantifying new specific biomarkers for PCa detection, stratification and treatment. In an effort to identify HO-1 molecular partners associated to the integrity of the cellular architecture and assess actin dynamics of PCa cells under HO-1 modulation, we undertook an in-depth mass spectrometry-based proteomics study to build the HO-1 interactome in PCa,The proteomics analysis of HO-1 interacting factors revealed several cytoskeletal-associated proteins involved in the regulation of actin filament dynamics. We also performed a bioinformatic screening across the Oncomine platform, which showed that the RNA expression profiles of the cytoskeletal HO-1 interacting proteins lie within the 22 percent of the most consistently low or high-expressed genes in prostate adenocarcinoma compared to normal prostate tissue. We took advantage of 2D migration assays to assess motility changes. As a result, we observed a reduced frequency in migration events, trajectory and cell velocity under hemin exposure. Moreover, a significant higher proportion of filopodia-like protrusions among neighboring cells and cell-cell contacts were observed under HO-1 modulation. Forced-expression of HO-1 resulted in an alteration of cell protrusions in transwell co-culture systems of PC3 cells with MC3T3 cells (pre-osteoblastic cell line). Altogether, we demonstrate for the first time that HO-1 interacts with cytoskeletal proteins highly misregulated in PCa, alters cell migratory patterns, induces the remodeling of the actin filament architecture at filopodia towards a less invasive phenotype, showcasing its relevance as a key homeostatic factor against the aggressive and metastatic disease.