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

ALEJANDRA PAEZ,; CARLA PALLAVICINI,; SCHUSTER FEDERICO,; GIUDICE JIMENA,; PIA VALACCO,; GUERON GERALDINE

New Orleans

Congreso; AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA; 2016

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 heme-oxygenase 1 (HO-1) has a strong anti-tumoral effect in prostate cancer (PCa) and regulates the adhesive properties of PCa cells. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification and treatment. Towards this end, we undertook an in-depth mass spectrometry-based proteomics study to build the Heme-oxygenase 1 (HO-1) interactome in PCa, 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.The proteomics analysis of HO-1 interacting proteins yielded several cytoskeletal-associated 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 HO-1 interacting proteins, lie within the 10 percent of the most consistently low-expressed genes in prostate adenocarcinoma compared to normal tissue.Motility changes were assessed on fiber-like 2D migration scenarios displaying a reduced frequency in migration events and in migration speed under hemin exposure, a specific pharmacological inducer of HO-1. A significant higher proportion of filopodia-like protrusions among neighboring cells and cellular contacts were observed when HO-1 was induced; effects reversed under HO-1 silencing. Altogether, our experimental findings demonstrate that HO-1 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.Citation Format: Alejandra V. Paez, Carla Pallavicini, Federico Schuster, Jimena Giudice, Pia Valacco, Estefania Labanca, Nicolas Anselmino, Emiliano Ortiz, Maria Binaghi, Javier Cotignola, Marcelo Marti, Luciana Bruno, Valeria Levi, Nora Navone, Elba Vazquez, Geraldine Gueron. Hitting the brakes on the migratory capacity of tumoral cells: Targeting key regulators of actin dynamics in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5058.