PDZ-RhoGEF Is a Signaling Effector for TROY-Induced Glioblastoma Cell Invasion and Survival.

Abstract

Glioblastoma multiforme (GBM) is the most common type of malignant brain tumors in adults and has a dismal prognosis. The highly aggressive invasion of malignant cells into the normal brain parenchyma renders complete surgical resection of GBM tumors impossible, increases resistance to therapeutic treatment, and leads to near-universal tumor recurrence. We have previously demonstrated that TROY (TNFRSF19) plays an important role in glioblastoma cell invasion and therapeutic resistance. However, the potential downstream effectors of TROY signaling have not been fully characterized. Here, we identified PDZ-RhoGEF as a binding partner for TROY that potentiated TROY-induced nuclear factor kappa B activation which is necessary for both cell invasion and survival. In addition, PDZ-RhoGEF also interacts with Pyk2, indicating that PDZ-RhoGEF is a component of a signalsome that includes TROY and Pyk2. PDZ-RhoGEF is overexpressed in glioblastoma tumors and stimulates glioma cell invasion via Rho activation. Increased PDZ-RhoGEF expression enhanced TROY-induced glioma cell migration. Conversely, silencing PDZ-RhoGEF expression inhibited TROY-induced glioma cell migration, increased sensitivity to temozolomide treatment, and extended survival of orthotopic xenograft mice. Furthermore, depletion of RhoC or RhoA inhibited TROY- and PDZ-RhoGEF-induced cell migration. Mechanistically, increased TROY expression stimulated Rho activation, and depletion of PDZ-RhoGEF expression reduced this activation. Taken together, these data suggest that PDZ-RhoGEF plays an important role in TROY signaling and provides insights into a potential node of vulnerability to limit GBM cell invasion and decrease therapeutic resistance.

• Authors: Zonghui Ding, Harshil Dhruv, Aneta Kwiatkowska-Piwowarczyk, Rosamaria Ruggieri, Jean Kloss, Marc Symons, Patrick Pirrotte, Jennifer M Eschbacher, Nhan L Tran, Joseph C Loftus
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 20 Issue 10 Pg. 1045-1058 (10 2018) ISSN: 1476-5586 [Electronic] United States
• PMID: 30219706 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• ARHGEF11 protein, human
• Receptors, Tumor Necrosis Factor
• Rho Guanine Nucleotide Exchange Factors
• TNFRSF19 protein, human
• RHOA protein, human
• Focal Adhesion Kinase 2
• RHOC protein, human
• rhoA GTP-Binding Protein
• rhoC GTP-Binding Protein
• Temozolomide

Topics

• Animals
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Survival
• Female
• Focal Adhesion Kinase 2 (metabolism)
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Mice, Nude
• Receptors, Tumor Necrosis Factor (genetics, metabolism)
• Rho Guanine Nucleotide Exchange Factors (genetics, metabolism)
• Signal Transduction
• Temozolomide (pharmacology)
• Xenograft Model Antitumor Assays
• rhoA GTP-Binding Protein (genetics, metabolism)
• rhoC GTP-Binding Protein (genetics, metabolism)