UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

6-7-2016

Document Type

Article

Disciplines

Cancer Biology | Cell Biology

Abstract

Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor. Radiation in combination with temozolomide (TMZ), the current chemotherapeutic for GBMs, only provides 12-14 months survival post diagnosis. Because GBMs are dependent on both activation of the DNA damage pathway and the endoplasmic reticulum (ER) stress response, we asked if a novel ER stress inducing agent, JLK1486, increases the efficacy of TMZ. We found that the combination of TMZ+JLK1486 resulted in decreased proliferation in a panel of adherent GBM cells lines and reduced secondary sphere formation in non-adherent and primary lines. Decreased proliferation correlated with increased cell death due to apoptosis. We found prolonged ER stress in TMZ+JLK1486 treated cells that resulted in sustained activation of the unfolded protein response (UPR) through increased levels of BiP, ATF4, and CHOP. In addition, TMZ+JLK1486 treatment caused decreased RAD51 levels, impairing DNA damage repair. Furthermore, we found delayed time to tumor doubling in TMZ+JLK1486 treated mice. Our data shows that the addition of JLK1486 to TMZ increases the efficaciousness of the treatment by decreasing proliferation and inducing cell death. We propose increased cell death is due to two factors. One, prolonged ER stress driving the expression of the pro-apoptotic transcription factor CHOP, and, second, unresolved DNA double strand breaks, due to decreased RAD51 levels. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between unresolved ER stress and the DNA damage response pathway.

Rights and Permissions

Citation: Oncotarget. 2016:7(28), 43820-43834. doi: 10.18632/oncotarget.9907. Link to article on publisher's site

All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.

DOI of Published Version

10.18632/oncotarget.9907

Related Resources

Link to Article in PubMed

Keywords

ATF4, DNA double strand breaks, apoptosis, endoplasmic reticulum stress, glioblastoma

Journal/Book/Conference Title

Oncotarget

PubMed ID

27286262

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

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