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Cdc42 and Rac1 Activity Is Reduced in Human Pheochromocytoma and Correlates with FARP1 and ARHGEF1 Expression

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Cdc42 and Rac1 Activity Is Reduced in Human Pheochromocytoma and Correlates with FARP1 and ARHGEF1 Expression 234 P Croisé et al. Rho-GTPase activity in human 23:4 281–293 Research pheochromocytoma Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression Pauline Croisé1, Sébastien Houy1, Mathieu Gand1, Joël Lanoix2, Valérie Calco1, Petra Tóth1, Laurent Brunaud3, Sandra Lomazzi4, Eustache Paramithiotis2, Daniel Chelsky2, Stéphane Ory1,* and Stéphane Gasman1,* Correspondence 1Institut des Neurosciences Cellulaires et Intégratives (INCI), CNRS UPR 3212, Strasbourg, France should be addressed 2Caprion Proteome, Inc., Montréal, Québec, Canada to S Ory or S Gasman 3Service de Chirurgie Digestive, Hépato-bilaire et Endocrinienne, CHRU Nancy, Hôpitaux de Brabois, Email Vandoeuvre les Nancy, France [email protected] or 4Centre de Ressources Biologiques (CRB), CHRU Nancy, Hôpitaux de Brabois, Vandoeuvres les Nancy, France [email protected] *(S Ory and S Gasman contributed equally to this work) Abstract Among small GTPases from the Rho family, Cdc42, Rac, and Rho are well known to mediate Key Words a large variety of cellular processes linked with cancer biology through their ability to cycle f Rho-GTPases between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide f pheochromocytoma exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated f mass spectrometry form, whereas the GTPase-activating proteins (GAPs) catalyze GTP hydrolysis, leading to f Rho-GEF Endocrine-Related Cancer Endocrine-Related the inactivated form. Modulation of Rho GTPase activity following altered expression of Rho-GEFs and/or Rho-GAPs has already been reported in various human tumors. However, nothing is known about the Rho GTPase activity or the expression of their regulators in human pheochromocytomas, a neuroendocrine tumor (NET) arising from chromaffin cells of the adrenal medulla. In this study, we demonstrate, through an ELISA-based activity assay, that Rac1 and Cdc42 activities decrease in human pheochromocytomas (PCCs) compared with the matched adjacent non-tumor tissue. Furthermore, through quantitative mass spectrometry (MS) approaches, we show that the expression of two Rho-GEF proteins, namely ARHGEF1 and FARP1, is significantly reduced in tumors compared with matched non-tumor tissue, whereas ARHGAP36 expression is increased. Moreover, siRNA-based knockdown of ARHGEF1 and FARP1 in PC12 cells leads to a significant inhibition of Rac1 and Cdc42 activities, respectively. Finally, a principal component analysis (PCA) of our dataset was able to discriminate PCC from non-tumor tissue and indicates a close correlation between Cdc42/Rac1 activity and FARP1/ARHGEF1 expression. Altogether, our findings reveal for the first time the importance Endocrine-Related Cancer of modulation of Rho GTPase activities and expression of their regulators in human PCCs. (2016) 23, 281–293 Introduction The monomeric Rho (Ras homologous) GTPase family, a RhoA, Rac1, and Cdc42. Most of the Rho GTPases subclass of the Ras GTPase superfamily, contains 20 highly undergo a tightly regulated activation/inactivation cycle conserved members including the well-investigated by switching from an inactive GDP-bound to an active http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-15-0502 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 09:53:17PM via free access 10.1530/ERC-15-0502 Research P Croisé et al. Rho-GTPase activity in human 23:4 282 pheochromocytoma GTP-bound conformation upon signaling cues. Their screening proteomic approach we have measured the activation is under the control of guanine nucleotide expression of several Rho-GEFs and -GAPs in human exchange factors (GEFs) that stimulate the exchange of PCC, and found that the expression of two GEFs, GDP for GTP, and their inactivation requires GTPase- ARHGEF1, and FARP1, is significantly reduced in tumors activating proteins (GAPs) that catalyze GTP hydrolysis compared with matched non-tumor tissue. Finally, using by the Rho GTPases (Cherfils & Zeghouf 2013). PCC cell models, we demonstrate that knocking down Rho GTPases regulate many cellular processes ARHGEF1 and FARP1 by siRNA significantly reduces related to cancer biology, including cell cycle regulation, Rac1 and Cdc42 activities. cell polarity establishment, cell migration, apoptosis and angiogenesis (Ellenbroek & Collard 2007, Vega & Ridley 2008). Consequently, Rho GTPases have Materials and methods been largely implicated in many types of cancer, and Subjects and samples numerous studies have shown that aberrant expression of Rho GTPases is associated with tumor growth, The study involved an analysis of data from 41 patients invasion, and metastasis. The evidence for the role of who underwent surgery for benign PCC originating from Rho GTPases in various stages of tumorigenesis has adrenal medulla between 2000 and 2009. All included been compiled in comprehensive reviews (Ellenbroek patients had no clinical suspicion for malignant PCC & Collard 2007, Grise et al. 2009, Karlsson et al. 2009, (metastasis, locoregional involvement) or familial disease Parri & Chiarugi 2010, Alan & Lundquist 2013, Orgaz (negative germ-line mutation when performed, no et al. 2014). However, the expression level of Rho GTPase personal or family history of familial disease) at operation. genes or proteins does not necessarily reflect their Furthermore, postoperative follow-up has not shown any activation state. Even so, the activation state of Rho tumor recurrence, metastasis, or late syndromic features in GTPases in tumors has been very rarely investigated. all included patients. Surgery was performed by Pr Laurent Modulation of Rho-GTPase activity can occur through Brunaud at Nancy-Brabois University Hospital (Vandoeuvre altered expression of Rho-GEFs or Rho-GAPs, a les Nancy, France). After resection, the adrenal gland was cut phenomenon that has also been observed in various longitudinally into two parts, and a piece of the tumor zone tumors (Ellenbroek & Collard 2007, Vigil et al. 2010). was dissected. Regarding the non-tumor adjacent control Expression of Rho GTPases and their regulators tissue, a piece of adrenal medulla was carefully dissected Endocrine-Related Cancer Endocrine-Related has been explored in many types of tumors with the outside the tumor zone under a binocular magnifier ×( 4) exception of human NETs, a heterogeneous group and removed from the gland. This biological collection is arising from hormone/peptide-producing cells dispersed governed by French legislation and regulations (registration in the neuroendocrine system, including mainly the numbers to the Ministry of Research DC-2014-2114 and gastrointestinal and bronchopulmonary systems, and the AC-2014-2112, and CNIL data protection legislation adrenal, thyroid, and thymus glands (Taal & Visser 2004, 1209171). Informed consent was obtained from all Yao et al. 2008). Among NETs, PCCs arise from chromaffin participants, and the study was approved by the local ethic cells of the adrenal medulla and are characterized by committees (October 10, 2008 by CPP Est-III). an excess of catecholamine release, leading mainly to Non-PCC tissues used in this study were drawn from hypertension, cardiomyopathy and severe stroke risk patients who underwent surgery for various types of (Tsirlin et al. 2014). During the last decade, PCCs have epithelial cancers (lung, colon, bladder, prostate, breast, been widely studied and have emerged as a relevant model and kidney) at two different institutions (McGill University for investigation of NETs. So far, the potential importance Health Center and Centre Hospitalier de l'Université de of Rho GTPases has not been investigated in human PCC. Montréal; Montreal, Quebec, Canada). Informed consent The aim of this study was to analyze the activity of was obtained from all patients as part of an institutionally RhoA, Rac1, and Cdc42 as well as the expression of their approved protocol and after approval from the institutional putative regulators (Rho-GEFs and -GAPs) in human review boards of the two participating institutions. resections of PCC. Using an ELISA-based activity assay, Once dissected, PCC and epithelial cancer tumors we found that Rac1 and Cdc42 activities decrease in as well as their respective matching adjacent non-tumor tumors compared with the adjacent non-tumor adrenal tissues were placed in physiologic media immediately tissue from the same patient, whereas RhoA activity after excision in the operating room. Samples were then remains unchanged. Moreover, through a quantitative directly frozen and stored at –80°. http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-15-0502 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 09:53:17PM via free access Research P Croisé et al. Rho-GTPase activity in human 23:4 283 pheochromocytoma Cell culture and transfection ((Rhosample – Rhobkg)/(Rhomax – Rhobkg)) × 100. The GTP hydrolysis rate (Rhomax/Rhotot) between normal and Rattus norvegicus PC12 cell line (ATCC CRL-1721) is tumor samples was unchanged. a noradrenergic single clonal line established from a For Rho GTPase activity measurement in PC12 cells, transplantable rat adrenal PCC (for more details see 48 h after siRNA transfection, cells were washed twice in Greene & Tischler 1976). PC12 cells were cultured as Locke’s solution and lysed in Cytoskeleton G-LISA lysis described previously
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