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Inhibition of YB-1 alone or in combination with TMZ may improve GBM treatment

University of British Columbia

Glioblastoma is a rare, but devastating brain tumor. Recent studies showed that GBM is correlated with Y-box binding protein-1 (YB-1) overexpression both in pediatric and adult patients. YB-1 is a member of the cold shock domain protein superfamily. It performs a wide variety of cellular functions, including regulation of cell growth, apoptosis, transcription, translation and drug resistance. Our goal was to determine the potential therapeutic value of targeting YB-1 in GBM. We carried out both transient and stable YB-1 knock-down, using siRNA and shRNA in GBM cell lines. The loss of YB-1 inhibited the cologenicity of SF188 in soft agar, and suppressed cell invasiveness in matrigel invasion assay. Furthermore, YB-1 stable knock-down delayed the onset of tumor formation in mice and suppressed tumor growth by 30%. Beyond its role in tumor growth and invasion, YB-1 is also strongly linked to drug resistance. We therefore addressed whether it plays roles in taxol (TXL) and temozolomide (TMZ) sensitivity. TXL is a commonly used anti-tumor drug and TMZ is the leading compound in GBM treatment. We evaluated YB-1 stable knock-down GBM cells sensitivity to these drugs both in monolayer and soft agar. Interestingly, we see a significant increase of apoptosis induced by TXL and TMZ in YB-1 silenced cells. Also, an enhanced suppression of cologenicity by TXL in soft agar was examined in YB-1 silenced cells. These results suggest that YB-1 modulates cell invasive ability, cologenicity, tumorgenicity in vivo and response to chemotherapy. With improved understanding of YB-1 roles in GBM, novel therapeutic approaches developed to target it are expected to provide a promising therapeutic benefit in treatment of GBM.

Thesis/Dissertation

application/pdf

2009-11-09

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/14697

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/