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Neoplasia. 2018 Oct;20(10):1045-1058. doi: 10.1016/j.neo.2018.08.008. Epub 2018 Sep 13.

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

Author information

1
Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259.
2
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004.
3
Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at Northwell Health, Manhasset, NY 11030.
4
Center for Proteomics, Translational Genomics Research Institute, Phoenix, AZ 85004.
5
Department of Neuropathology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013.
6
Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259; Department of Neurosurgery, Mayo Clinic Arizona, Scottsdale, AZ 85259. Electronic address: Tran.Nhan@mayo.edu.
7
Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259. Electronic address: Loftus.Joseph@mayo.edu.

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.

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