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

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

Congreso; AACR Annual Meeting 2016; 2016

Prostate Cancer (PCa) is the second leading cause of cancer in men. PCa cells display abnormal expression of cytoskeletal proteins resultingin an augmented capacity to resist chemotherapy and colonize other organs. We have previously shown that hemeoxygenase1 (HO1)has astrong antitumoraleffect in prostate cancer (PCa) and regulates the adhesive properties of PCa cells. Innovative highthroughputproteomicplatforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification and treatment. Towardsthis end, we undertook an indepthmass spectrometrybasedproteomics study to build the Hemeoxygenase1 (HO1)interactome in PCa,in an effort to identify HO1molecular partners associated to the integrity of the cellular architecture and assess actin dynamics of PCa cellsunder HO1modulation.The proteomics analysis of HO1interacting proteins yielded several cytoskeletalassociatedproteins regulating actin filament dynamics, suchas gelsolin, lasp1, SIPA1L1, testin, moesin, tropomodulin and vinculin. The bioinformatics screening across the Oncomine platform revealedthat the RNA expression profiles of the cytoskeletal HO1interacting proteins, lie within the 10 percent of the most consistently lowexpressedgenes in prostate adenocarcinoma compared to normal tissue.Motility changes were assessed on fiberlike2D migration scenarios displaying a reduced frequency in migration events and in migration speedunder hemin exposure, a specific pharmacological inducer of HO1.A significant higher proportion of filopodialikeprotrusions amongneighboring cells and cellular contacts were observed when HO1was induced; effects reversed under HO1silencing. Altogether, ourexperimental findings demonstrate that HO1modulation in PCa induces the remodeling of the actin filament architecture at filopodia, alters themigratory patterns and cellular morphology, showcasing the relevance of the cytoskeletal proteins as potential therapeutic targets against theaggressive and metastatic disease.