Abstract
SPARC, a matricellular protein with tumor suppressor properties in certain human cancers, was initially identified in a genome-wide analysis of differentially expressed genes in chemotherapy resistance. Its exciting new role as a potential chemosensitizer arises from its ability to augment the apoptotic cascade, although the exact mechanisms are unclear. This study further examines the mechanism by which SPARC may be promoting apoptosis and identifies a smaller peptide analogue with greater chemosensitizing and tumor-regressing properties than the native protein. We examined the possibility that the apoptosis-enhancing activity of SPARC could reside within one of its three biological domains (N-terminus (NT), the follistatin-like (FS), or extracellular (EC) domains), and identified the N-terminus as the region with its chemosensitizing properties. These results were not only confirmed by studies utilizing stable cell lines overexpressing the different domains of SPARC, but as well, with a synthetic 51-aa peptide spanning the NT-domain. It revealed that the NT-domain induced a significantly greater reduction in cell viability than SPARC, and that it enhanced the apoptotic cascade via its activation of caspase 8. Moreover, in chemotherapy resistant human colon, breast and pancreatic cancer cells, its chemosensitizing properties also depended on its ability to dissociate Bcl2 from caspase 8. These observations translated to clinically significant findings in that, in-vivo, mouse tumor xenografts overexpressing the NT-domain of SPARC had significantly greater sensitivity to chemotherapy and tumor regression, even when compared to the highly-sensitive SPARC-overexpressing tumors. Our results identified an interplay between the NT-domain, Bcl2 and caspase 8 that helps augment apoptosis and as a consequence, a tumor's response to therapy. This NT-domain of SPARC and its 51-aa peptide are highly efficacious in modulating and enhancing apoptosis, thereby conferring greater chemosensitivity to resistant tumors. Our findings provide additional insight into mechanisms involved in chemotherapy resistance and a potential novel therapeutic that specifically targets this devastating phenomenon.
Highlights
Many pathological conditions arise because of abnormal regulation in cellular activities, such as apoptosis, that disrupt the fine balance between cell survival and death
Our current study demonstrates that the pro-apoptotic activity of SPARC is confined to a specific region of the protein, and that a recombinant peptide containing this smaller region alone is capable of conferring greater apoptosis and tumor regression in vivo
We and others have previously shown that high levels of SPARC, a matricellular protein known to influence cell growth and apoptosis, to be associated with increased apoptosis in ovarian, pancreatic and colorectal cancers (CRC) [4,6,7], and that its exogenous exposure in-vivo promotes greater tumor regression in CRCs that had become refractory to conventional chemotherapies [4]
Summary
Many pathological conditions arise because of abnormal regulation in cellular activities, such as apoptosis, that disrupt the fine balance between cell survival and death. The mechanisms involved in SPARC-mediated apoptosis are further examined, with a specific focus on identifying a region within SPARC that may be responsible for promoting apoptosis This is based on reports that the three structural domains of SPARC contribute to this protein’s multi-functional yet distinct biological properties (Fig. 1A): (1) N-terminus (NT), (2) follistatin-like (FS), and (3) the extracellular C-terminus (EC) domains [9,10]. While we previously demonstrated an interaction between SPARC and caspase 8 in potentiating the apoptotic cascade [8], this study invokes Bcl, an anti-apoptotic member of the intrinsic/mitochondrial pathway of apoptosis, as an important component in this interaction with caspase 8 and SPARC This network of interactions affects the apoptotic cascade which influences drug sensitivity, therapy response and reversal of drug resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
