Specific role of RhoC in tumor invasion and metastasis
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Sarah Lang1, Hauke Busch2,3, Melanie Boerries3,4, Tilman Brummer3,4,5, Sylvia Timme6, Silke Lassmann4,5,6, Klaus Aktories1 and Gudula Schmidt1
1Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
2Lübeck Institute of Experimental Dermatology, Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
3Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany
4German Cancer Consortium (DKTK), Freiburg, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany
5Center for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany
6Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Gudula Schmidt, email: [email protected]
Keywords: Rho GTPase, invasion, cyclooxygenase, breast cancer
Received: June 14, 2017 Accepted: August 26, 2017 Published: September 16, 2017
Rho GTPases are regulators of many cellular functions and are often dysregulated in cancer. However, the precise role of Rho proteins for tumor development is not well understood. In breast cancer, overexpression of RhoC is linked with poor prognosis. Here, we aim to compare the function of RhoC and its homolog family member RhoA in breast cancer progression. We established stable breast epithelial cell lines with inducible expression of RhoA and RhoC, respectively. Moreover, we made use of Rho-activating bacterial toxins (Cytotoxic Necrotizing Factors) to stimulate the endogenous pool of Rho GTPases in benign breast epithelial cells and simultaneously knocked down specific Rho proteins. Whereas activation of Rho GTPases was sufficient to induce an invasive phenotype in three-dimensional culture systems, overexpression of RhoA or RhoC were not. However, RhoC but not RhoA was required for invasion, whereas RhoA and RhoC equally regulated proliferation. We further identified downstream target genes of RhoC involved in invasion and identified PTGS2 (COX-2) being preferentially upregulated by RhoC. Consistently, the COX-2 inhibitor Celecoxib blocked the invasive phenotype induced by the Rho-activating toxins.
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