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SPARC enhances chemosensitivity by activating the extrinsic pathway of apoptosis

University of British Columbia

Colorectal cancer (CRC) is the second leading cause of cancer death in Canada. Treatment failure in advanced disease is due to the development of chemotherapy resistance. Using a genomics approach, the Tai laboratory previously found that Secreted Protein Acidic and Rich in Cysteine (SPARC), a matricellular protein, was down-regulated in chemotherapy resistant CRCs. SPARC has tumour suppressor properties in ovarian and pancreatic cancers, where higher SPARC expression enhances apoptosis in vitro and tumour regression in vivo. In CRCs, it was found that exogenous SPARC re-sensitized CRCs to chemotherapy by inducing apoptosis and inhibiting tumour growth. In this thesis, the mechanisms of SPARC-mediated apoptosis, the fragment of SPARC responsible for SPARC-mediated apoptosis and the interaction between SPARC and collagen IV and its effect on chemosensitivity were examined. I demonstrated that SPARC can be internalized and interacts with the N-terminus of the procaspase 8 death effector domain (DED)-containing domain, activating the extrinsic pathway of apoptosis. This pro-apoptotic activity is mediated through SPARC’s N-terminus domain, where the N-terminus not only enhanced apoptosis in vitro, but also augmented tumour regression in vivo in combination with chemotherapy. The N-terminus domain of SPARC also interfered with the interaction between Bcl-2 and procaspase 8, decreased cell viability and increased apoptosis. I also found that higher SPARC levels correlated with higher caspase 8 expression. Further, I provided evidence that collagen IV and SPARC work in a co-operative manner to enhance apoptosis. This thesis focuses on the interplay between SPARC/Bcl- 2/procaspase 8 and collagen IV which may be important in modulating a tumour’s response to chemotherapy in CRCs, suggesting that SPARC may be a potential cancer therapeutic.

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2009-12-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/16685

Experimental Medicine

University of British Columbia

UBCV

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