Hitting the brakes on the migratory capacity of tumoral cells: Targeting key regulators of actin dynamics in prostate cancer

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

New Orleans

Congreso; AACR Annual Meeting 2016; 2016

American Association for Cancer Research

Prostate Cancer (PCa) is the second leading cause of cancer in men. PCa cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize other organs. We have previously shown that hemeoxygenase 1 (HO1) has a strong antitumoral effect in prostate cancer (PCa) and regulates the adhesive properties of PCa cells.Innovative highthroughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification and treatment. Towards this end, we undertook an indepth mass spectrometrybased proteomics study to build the Hemeoxygenase 1 (HO1) interactome in PCa, in an effort to identify HO1 molecular partners associated to the integrity of the cellular architecture and assess actin dynamics of PCa cells under HO1 modulation.The proteomics analysis of HO1 interacting proteins yielded several cytoskeletalassociated proteins regulating actin filament dynamics, such as gelsolin, lasp1, SIPA1L1, testin, moesin, tropomodulin and vinculin. The bioinformatics screening across the Oncomine platform revealed that the RNA expression profiles of the cytoskeletal HO1 interacting proteins, lie within the 10 percent of the most consistently lowexpressed genes in prostate adenocarcinoma compared to normal tissue.Motility changes were assessed on fiberlike 2D migration scenarios displaying a reduced frequency in migration events and in migration speed under hemin exposure, a specific pharmacological inducer of HO1.A significant higher proportion of filopodialike protrusions among neighboring cells and cellular contacts were observed when HO1 was induced; effects reversed under HO1 silencing. Altogether, our experimental findings demonstrate that HO1 modulation in PCa induces the remodeling of the actin filament architecture at filopodia, alters the migratory patterns and cellular morphology, showcasing the relevance of the cytoskeletal proteins as potential therapeutic targets against the aggressive and metastatic disease.