The TWEAK-Fn14 Ligand Receptor Axis Promotes Glioblastoma Cell Invasion and Survival Via Activation of Multiple GEF-Rho GTPase Signaling Systems

Persistent Link:
http://hdl.handle.net/10150/293463
Title:
The TWEAK-Fn14 Ligand Receptor Axis Promotes Glioblastoma Cell Invasion and Survival Via Activation of Multiple GEF-Rho GTPase Signaling Systems
Author:
Fortin Ensign, Shannon Patricia
Issue Date:
2013
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-kB dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.
Type:
text; Electronic Dissertation
Keywords:
GEF; Glioblastoma; Invasion; Rho GTPase; Survival; Cancer Biology; Fn14
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Tran, Nhan; Kim, Suwon

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleThe TWEAK-Fn14 Ligand Receptor Axis Promotes Glioblastoma Cell Invasion and Survival Via Activation of Multiple GEF-Rho GTPase Signaling Systemsen_US
dc.creatorFortin Ensign, Shannon Patriciaen_US
dc.contributor.authorFortin Ensign, Shannon Patriciaen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractGlioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-kB dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectGEFen_US
dc.subjectGlioblastomaen_US
dc.subjectInvasionen_US
dc.subjectRho GTPaseen_US
dc.subjectSurvivalen_US
dc.subjectCancer Biologyen_US
dc.subjectFn14en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorTran, Nhanen_US
dc.contributor.advisorKim, Suwonen_US
dc.contributor.committeememberTran, Nhanen_US
dc.contributor.committeememberKim, Suwonen_US
dc.contributor.committeememberMartinez, Jesseen_US
dc.contributor.committeememberCress, Anneen_US
dc.contributor.committeememberBishop, Mariaen_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.