Targeting Invasive Glioblastoma via the TROY-JAK1 Signaling Pathway

Persistent Link:
http://hdl.handle.net/10150/281192
Title:
Targeting Invasive Glioblastoma via the TROY-JAK1 Signaling Pathway
Author:
Kahn, Allon
Affiliation:
The University of Arizona College of Medicine - Phoenix
Issue Date:
Mar-2013
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the College of Medicine - Phoenix, 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.
Collection Information:
This item is part of the College of Medicine - Phoenix Scholarly Projects 2013 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu.
Publisher:
The University of Arizona.
Abstract:
Objective and Hypothesis: Glioblastoma multiforme, the most common and lethal primary brain neoplasm in adults, has been historically difficult to treat, as its invasion into contiguous brain tissue mitigates the benefit of surgical resection. Furthermore, its unique ability to evade apoptosis and selectively induce proliferation promotes chemotherapeutic resistance and explains the lack of substantial survival improvement despite decades of research. The orphan transmembrane receptor, TROY, has been shown to influence glioma cell migration and survival. While TROY downstream signaling presents a potential therapeutic target, the detailed pathway has yet to be fully elucidated. We identified the non-receptor tyrosine kinase, JAK1,as a candidate binding partner and hypothesized that JAK1 is a downstream mediator of TROY-induced glioma invasion, ultimately seeking to validate the potential therapeutic potential of this interaction. Methods: TROY-JAK1 binding was assessed by co-immunoprecipitation of JAK1 with immunoblotting for TROY. The mechanism of this JAK1-TROY interaction was assessed by western blottingfor phosphorylated JAK1 and STAT3 in wild type vs. TROY-overexpressing glioma cells. Finally, an in-vitro radial migration assay was performed under siRNA depletion of JAK1 to assess functional validation. Results: JAK1 was confirmedas a TROY binding partner by co-immunoprecipitation, with immunoblotting demonstrating that TROY-overexpression induces JAK1 phosphorylation. siRNA-mediated depletion of JAK1 also resulted in decreasedphosphorylated STAT3 level. Finally, a radial migration assay performed on wild-type and TROY-overexpressing T98G cells with and without JAK1 depletion demonstrated statistically significant reductions in migration rate in both JAK1-depleted groups compared to controls. Significance: This study identified and confirmed JAK1 as a downstream mediator of TROY signaling and demonstrated that JAK1 depletion results in mitigation of the pro-migratory effect of TROY overexpression. Thus, JAK1 provides a potential novel therapeutic target for disruption of glioblastoma TROY signaling in vivo andmay contribute to the development of more efficacious chemotherapeutic agents.
MeSH Subjects:
Signal Transduction; Glioblastoma
Description:
A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
Mentor:
Tran, Nhan, PhD

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleTargeting Invasive Glioblastoma via the TROY-JAK1 Signaling Pathwayen_US
dc.contributor.authorKahn, Allonen_US
dc.contributor.departmentThe University of Arizona College of Medicine - Phoenixen_US
dc.date.issued2013-03-
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the College of Medicine - Phoenix, 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.collectioninformationThis item is part of the College of Medicine - Phoenix Scholarly Projects 2013 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu.en_US
dc.publisherThe University of Arizona.en_US
dc.description.abstractObjective and Hypothesis: Glioblastoma multiforme, the most common and lethal primary brain neoplasm in adults, has been historically difficult to treat, as its invasion into contiguous brain tissue mitigates the benefit of surgical resection. Furthermore, its unique ability to evade apoptosis and selectively induce proliferation promotes chemotherapeutic resistance and explains the lack of substantial survival improvement despite decades of research. The orphan transmembrane receptor, TROY, has been shown to influence glioma cell migration and survival. While TROY downstream signaling presents a potential therapeutic target, the detailed pathway has yet to be fully elucidated. We identified the non-receptor tyrosine kinase, JAK1,as a candidate binding partner and hypothesized that JAK1 is a downstream mediator of TROY-induced glioma invasion, ultimately seeking to validate the potential therapeutic potential of this interaction. Methods: TROY-JAK1 binding was assessed by co-immunoprecipitation of JAK1 with immunoblotting for TROY. The mechanism of this JAK1-TROY interaction was assessed by western blottingfor phosphorylated JAK1 and STAT3 in wild type vs. TROY-overexpressing glioma cells. Finally, an in-vitro radial migration assay was performed under siRNA depletion of JAK1 to assess functional validation. Results: JAK1 was confirmedas a TROY binding partner by co-immunoprecipitation, with immunoblotting demonstrating that TROY-overexpression induces JAK1 phosphorylation. siRNA-mediated depletion of JAK1 also resulted in decreasedphosphorylated STAT3 level. Finally, a radial migration assay performed on wild-type and TROY-overexpressing T98G cells with and without JAK1 depletion demonstrated statistically significant reductions in migration rate in both JAK1-depleted groups compared to controls. Significance: This study identified and confirmed JAK1 as a downstream mediator of TROY signaling and demonstrated that JAK1 depletion results in mitigation of the pro-migratory effect of TROY overexpression. Thus, JAK1 provides a potential novel therapeutic target for disruption of glioblastoma TROY signaling in vivo andmay contribute to the development of more efficacious chemotherapeutic agents.en_US
dc.typeThesisen_US
dc.subject.meshSignal Transductionen_US
dc.subject.meshGlioblastomaen_US
dc.descriptionA Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.en_US
dc.contributor.mentorTran, Nhan, PhDen_US
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