Regulation of extracellular matrix degradation and metastatic spread by IQGAP1 through endothelin-1 receptor signalling in ovarian cancer

• Published in: Matrix biology Vol. 81; pp. 17 - 33
• Main Authors: Chellini, Lidia, Caprara, Valentina, Spadaro, Francesca, Sestito, Rosanna, Bagnato, Anna, Rosanò, Laura
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2019; Elsevier Science Ltd
• Subjects: Actin; beta-Arrestin 1 - metabolism; Cell activation; Cell Line, Tumor; Cell migration; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - metabolism; Cytoskeleton; Endothelin 1; Endothelin-1 - metabolism; Endothelin-1 receptors; Extracellular matrix; Extracellular Matrix - metabolism; Female; Gene Expression Regulation, Neoplastic; Growth factor receptors; GTPase-activating protein; Guanosine triphosphatases; Humans; Invadopodia; Invasiveness; IQGAP1; IQGAP1 protein; Localization; Matrix metalloproteinase; Metalloproteinase; Metastases; Metastasis; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Phenotypes; Podosomes - metabolism; Polarity; Prognosis; Proteolysis; Rac1 protein; ras GTPase-Activating Proteins - metabolism; Receptor, Endothelin A - metabolism; RhoA protein; Signal Transduction; Vinculin; Vinculin - metabolism; β-arr1; Invadopodia; Endothelin-1 receptors; β-arr1; IQGAP1; Endothelin-1; Ovarian cancer
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2018.10.005

The invasive phenotype of serous ovarian cancer (SOC) cells is linked to the formation of actin-based protrusions, invadopodia, operating extracellular matrix (ECM) degradation and metastatic spread. Growth factor receptors might cause engagement of integrin-related proteins, like the polarity protein IQ-domain GTPase-activating protein 1 (IQGAP1), to F-actin core needed for invadopodia functions. Here, we investigated whether IQGAP1 forms a signalosome with endothelin-1 (ET-1)/β-arrestin1 (β-arr1) network, as signal-integrating module for adhesion components, cytoskeletal remodelling and ECM degradation. In SOC cells, ET-1 receptor (ET-1R) activation, besides altering IQGAP1 expression and localization, coordinates the binding of IQGAP1 with β-arr1, representing a “hotspot” for ET-1R-induced invasive signalling. We demonstrated that the molecular interaction of IQGAP1 with β-arr1 affects relocalization of focal adhesion components, as vinculin, and cytoskeleton dynamics, through the regulation of invadopodia-related pathways. In particular, ET-1R deactivates Rac1 thereby promoting RhoA/C activation for the correct functions of invasive structures. Silencing of either IQGAP1 or β-arr1, or blocking ET-1R activation with a dual antagonist macitentan, prevents matrix metalloproteinase (MMP) activity, invadopodial function, transendothelial migration and cell invasion. In vivo, targeting ET-1R/β-arr1 signalling controls the process of SOC metastasis, associated with reduced levels of IQGAP1, as well as other invadopodia effectors, such as vinculin, phospho-cortactin and membrane type 1-MMP. High expression of ETAR/β-arr1/IQGAP1 positively correlates with poor prognosis, validating the clinical implication of this signature in early prognosis of SOC. These data establish the ET-1R-driven β-arr1/IQGAP1 interaction as a prerequisite for the dynamic integration of pathways in fostering invadopodia and metastatic process in human SOC. •Endothelin-1 prompts IQGAP1/β-arr1 to coordinate invasive invadopodia in serous ovarian cancer cells.•Disrupting of IQGAP1/β-arr1 interaction inhibits ET-1R-dependent invadopodia activation and cell invasion.•In human patients, high expression of IQGAP1/β-arr1/ETAR positively correlates with poor prognosis, suggesting this signature as new prognostic factor in ovarian cancer.•Targeting of ET-1R inhibits SOC metastatic dissemination and invadopodia effectors expression, representing a novel therapeutic approach for serous ovarian cancer.