title: Peritoneal and hematogenous metastases of ovarian cancer cells are both controlled by the p90RSK through a self-reinforcing cell autonomous mechanism.
abstract: The molecular mechanisms orchestrating peritoneal and hematogenous metastases of ovarian cancer cells are assumed to be distinct. We studied the p90RSK family of serine/threonine kinases that lie downstream the RAS-ERK/MAPK pathway and modulate a variety of cellular processes including cell proliferation, survival, motility and invasiveness. We found the RSK1 and RSK2 isoforms expressed in a number of human ovarian cancer cell lines, where they played redundant roles in sustaining in vitro motility and invasiveness. In vivo, silencing of both RSK1 and RSK2 almost abrogated short-term and long-term metastatic engraftment of ovarian cancer cells in the peritoneum. In addition, RSK1/RSK2 silenced cells failed to colonize the lungs after intravenous injection and to form hematogenous metastasis from subcutaneous xenografts. RSK1/RSK2 suppression resulted in lessened ovarian cancer cell spreading on endogenous fibronectin (FN). Mechanistically, RSK1/RSK2 knockdown diminished FN transcription, α5β1 integrin activation and TGF-β1 translation. Reduced endogenous FN deposition and TGF-β1 secretion depended on the lack of activating phosphorylation of the transcription/translation factor YB-1 by p90RSK. Altogether data show how p90RSK activates a self-reinforcing cell autonomous pro-adhesive circuit necessary for metastatic seeding of ovarian cancer cells. Thus, p90RSK inhibitors might hinder both the hematogenous and the peritoneal metastatic spread of human ovarian cancer.
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Torchiaro
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lorenzato
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Valdembri
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Paolo Armando
authors.initials: PA
authors.lastname: Gagliardi
authors.affiliation: Department of Molecular Biotechnologies and Health Sciences, University of Turin at the Molecular Biotechnology Center, Torino, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Gai
authors.affiliation: Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Erriquez
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Turin, Italy.|Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia (FPO)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy.
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D005353:Fibronectins; D053773:Transforming Growth Factor beta1; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
keywords: cell adhesion; fibronectin; hematogenous metastasis; p90RSK; peritoneal metastasis