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

Zonghui Ding, Harshil Dhruv, Aneta Kwiatkowska-Piwowarczyk, Rosamaria Ruggieri, Jean Kloss, Marc Symons, Patrick Pirrotte, Jennifer M. Eschbacher, Nhan Tran, Joseph C Loftus

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1045-1058
Number of pages14
JournalNeoplasia (United States)
Volume20
Issue number10
DOIs
StatePublished - Oct 1 2018

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Rho Guanine Nucleotide Exchange Factors
Glioblastoma
Cell Survival
Glioma
Cell Movement
temozolomide
Neoplasms
NF-kappa B
Heterografts
Brain Neoplasms
Therapeutics
Recurrence

ASJC Scopus subject areas

  • Cancer Research

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PDZ-RhoGEF Is a Signaling Effector for TROY-Induced Glioblastoma Cell Invasion and Survival. / Ding, Zonghui; Dhruv, Harshil; Kwiatkowska-Piwowarczyk, Aneta; Ruggieri, Rosamaria; Kloss, Jean; Symons, Marc; Pirrotte, Patrick; Eschbacher, Jennifer M.; Tran, Nhan; Loftus, Joseph C.

In: Neoplasia (United States), Vol. 20, No. 10, 01.10.2018, p. 1045-1058.

Research output: Contribution to journalArticle

Ding, Z, Dhruv, H, Kwiatkowska-Piwowarczyk, A, Ruggieri, R, Kloss, J, Symons, M, Pirrotte, P, Eschbacher, JM, Tran, N & Loftus, JC 2018, 'PDZ-RhoGEF Is a Signaling Effector for TROY-Induced Glioblastoma Cell Invasion and Survival', Neoplasia (United States), vol. 20, no. 10, pp. 1045-1058. https://doi.org/10.1016/j.neo.2018.08.008
Ding Z, Dhruv H, Kwiatkowska-Piwowarczyk A, Ruggieri R, Kloss J, Symons M et al. PDZ-RhoGEF Is a Signaling Effector for TROY-Induced Glioblastoma Cell Invasion and Survival. Neoplasia (United States). 2018 Oct 1;20(10):1045-1058. https://doi.org/10.1016/j.neo.2018.08.008
Ding, Zonghui ; Dhruv, Harshil ; Kwiatkowska-Piwowarczyk, Aneta ; Ruggieri, Rosamaria ; Kloss, Jean ; Symons, Marc ; Pirrotte, Patrick ; Eschbacher, Jennifer M. ; Tran, Nhan ; Loftus, Joseph C. / PDZ-RhoGEF Is a Signaling Effector for TROY-Induced Glioblastoma Cell Invasion and Survival. In: Neoplasia (United States). 2018 ; Vol. 20, No. 10. pp. 1045-1058.
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AU - Kloss, Jean

AU - Symons, Marc

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