Oncotarget

Research Papers:

Peritoneal and hematogenous metastases of ovarian cancer cells are both controlled by the p90RSK through a self-reinforcing cell autonomous mechanism

Erica Torchiaro, Annalisa Lorenzato, Martina Olivero, Donatella Valdembri, Paolo Armando Gagliardi, Marta Gai, Jessica Erriquez, Guido Serini and Maria Flavia Di Renzo _

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Oncotarget. 2016; 7:712-728. https://doi.org/10.18632/oncotarget.6412

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Abstract

Erica Torchiaro1,2, Annalisa Lorenzato1,2, Martina Olivero1,2, Donatella Valdembri1,2, Paolo Armando Gagliardi1,2, Marta Gai3, Jessica Erriquez2, Guido Serini1,2, Maria Flavia Di Renzo1,2

1Department of Oncology, University of Torino School of Medicine, Turin, Italy

2Candiolo Cancer Institute, Fondazione del Piemonte per l’Oncologia (FPO)–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy

3Department of Molecular Biotechnologies and Health Sciences, University of Turin at the Molecular Biotechnology Center, Torino, Italy

Correspondence to:

Maria Flavia Di Renzo, e-mail: [email protected]

Keywords: p90RSK, peritoneal metastasis, hematogenous metastasis, cell adhesion, fibronectin

Received: June 29, 2015     Accepted: November 15, 2015     Published: November 26, 2015

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.


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