title: Heme oxygenase-1 in the forefront of a multi-molecular network that governs cell-cell contacts and filopodia-induced zippering in prostate cancer.
abstract: Prostate cancer (PCa) cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown that heme oxygenase 1 (HO-1) is implicated in cell morphology regulation in PCa. Here, through a multi 'omics' approach we define the HO-1 interactome in PCa, identifying HO-1 molecular partners associated with the integrity of the cellular cytoskeleton. The bioinformatics screening for these cytoskeletal-related partners reveal that they are highly misregulated in prostate adenocarcinoma compared with normal prostate tissue. Under HO-1 induction, PCa cells present reduced frequency in migration events, trajectory and cell velocity and, a significant higher proportion of filopodia-like protrusions favoring zippering among neighboring cells. Moreover forced expression of HO-1 was also capable 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 markers related to cell adhesion and cell-cell communication under HO-1 induction. The integration from our omics-based research provides 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 approaches presented here promise to move us closer to unravel the molecular framework underpinning HO-1 involvement in the modulation of cytoskeleton pathways, pushing toward a less aggressive phenotype in PCa.
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Alejandra V
authors.initials: AV
authors.lastname: Paez
authors.affiliation: Department of Physics, FCEN, University of Buenos Aires, IFIBA-CONICET, Buenos Aires, Argentina.
authors.forename: Carla
authors.initials: C
authors.lastname: Pallavicini
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Federico
authors.initials: F
authors.lastname: Schuster
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Valacco
authors.affiliation: Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jimena
authors.initials: J
authors.lastname: Giudice
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Emiliano G
authors.initials: EG
authors.lastname: Ortiz
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Anselmino
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Estefania
authors.initials: E
authors.lastname: Labanca
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Maria
authors.initials: M
authors.lastname: Binaghi
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Salierno
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Martí
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Javier H
authors.initials: JH
authors.lastname: Cotignola
authors.affiliation: Pharmacology and Therapeutics Department, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Woloszynska-Read
authors.affiliation: Department of Physics, FCEN, University of Buenos Aires, IFIBA-CONICET, Buenos Aires, Argentina.
authors.forename: Luciana
authors.initials: L
authors.lastname: Bruno
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Valeria
authors.initials: V
authors.lastname: Levi
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Navone
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Elba S
authors.initials: ES
authors.lastname: Vazquez
authors.affiliation: Department of Biological Chemistry, School of Sciences, FCEN, University of Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Gueron
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D018360:Crystallography, X-Ray; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D040901:Proteomics; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D053719:Tandem Mass Spectrometry; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D051547:Heme Oxygenase-1