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Control/Tracking Number: 2015-S-15270-SfN Activity: Scientific Abstract Current Date/Time: 5/7/2015 7:35:36 PM Glycolytic inhibition induces er stress and apoptotic cell death in patient derived glioblastoma stem-like cells.
AUTHOR BLOCK: *S. S. SHAH1,2, G. A. RODRIGUEZ1, A. SANCHEZ1, M. SCHECHTER2, W. WALTERS1, R. J. KOMOTAR1, J. S. PRINCE2, R. M. GRAHAM1; 1Dept. of Neurolog. Surgery, Univ. of Miami Miller Sch. of Med., Miami, FL; 2Dept. of Biol., UM Electron Microscopy Lab.,
Coral Gables, FL Abstract: Background: Glioblastoma multiforme (GBM) is one of the most malignant and common primary brain tumors. Even with aggressive treatment, patient prognosis if dismal with a median survival time of 14.7 months. A subset of glioblastoma cells, glioblastoma stem cells (GSCs), is treatment resistant and implicated in disease recurrence. Currently, there is controversy regarding metabolic pathways GSCs employ_glycolysis versus oxidative phosphorylation. Therefore, we sought to perform transmission electron microscopic (TEM) analysis of GSC ultrastructure to determine metabolic preference, evaluate potential therapeutic targets, and propose mechanisms of action of novel treatments. Methods: GSCs were generated from patient-derived tumors, propagated in neurosphere media, and examined for stem-cell markers (Nestin, Musashi, Sox2, CD44, GFAP, BMI1) and ability to generate tumors in nude mice. Cellular morphology was evaluated by TEM. Effect of glycolytic inhibitors, 2-deoxyglucose (2-DG) and 3-bromopyruvate (3-BrPA), on cell viability was determined by MTS assay. Drug effect on cell signaling pathways was elucidated through Western Blot. Results: TEM analysis of multiple patient-derived GSCs confirmed a majority (>50%) of mitochondria exhibit either cristae loss or inner-fold polarization, indicating less available surface area for oxidative phosphorylation suggesting a metabolic dependence on glycolysis. Glycolytic inhibition significantly reduced GSC viability at 72 hours. 2-DG showed most consistent loss in viability compared to non-treated controls at clinically relevant concentrations (0.5mM = 52.1±10.3%; 1.0mM = 22.1±9.9%; 2.0mM = 8.1±5.0%). 3-BrPA showed similar dose dependent loss of GSC viability. In addition, 2-DG was found to up-regulate ER Stress markers (GRP78, CHOP) while also increasing apoptotic markers (cleaved PARP, cleaved Cas3). Conclusions: Targeting GSCs is vital in preventing tumor regeneration. EM provides a useful tool in developing experimental therapies. Our EM results indicate that oxidative phosphorylation is severely compromised in GSCs. Glycolytic inhibition proved effective in targeting GSCs and may represent an adjuvant therapy for a disease with minimal survival. :
Presentation Preference (Complete): No Preference Linking Group (Complete): None selected Nanosymposium Information (Complete): Briefly explain (500 characters including spaces) the timeliness and importance of your research and the overall theme of your proposed group. : Glioblastoma stem-like cells (GSCs), subsets of glioblastoma cells responsible for tumor recurrence, are resistant to most conventional treatments. Innovative therapeutic options are necessary to target these cells. Evidence suggests that these cells are glycolytic, and inhibiting glycolysis proved to be highly effective. We were able to characterize GSC ultrastructure and propose mechanisms responsible for GSC death by glycolytic inhibition: both of which are novel in current literature.
Theme and Topic (Complete): C.12.a. Neuro-oncology Keyword (Complete): GLIOBLASTOMA STEM-LIKE CELLS ; ELECTRON MICROSCOPY ; GLYCOLYTIC INHIBITION Support (Complete): Support: Yes Grant/Other Support: : Mystic Force Foundation Grant/Other Support: : ACC IAC Student Grant
Special Requests (Complete): Would you be interested in being considered for a dynamic poster?: Yes, I am interested in presenting a Dynamic Poster Is the submitting author of this abstract also a senior author?: Yes Is the first (presenting) author of this abstract a high school or undergraduate student?: None
Religious Conflict?: No Religious Conflict Additional Conflict?: No
Status: Finalized Oasis Helpdesk
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