A Peptide of SPARC Interferes with the Interaction between Caspase8 and Bcl2 to Resensitize Chemoresistant Tumors and Enhance Their Regression In Vivo

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.

Peptidomic Analysis of Cultured Cardiomyocytes Exposed to Acute Ischemic-Hypoxia

“…In many cases, segmental functional peptides play part of the biological function similar to their precursor proteins [41][42][43]. We selected 9 protein precursors closely related to cardiomyocyte structure or AMI from the 119 precursor proteins identified, and listed the differentially expressed peptides that were derived from functional domains in these proteins.…”

Genes Related to Suppression of Malignant Phenotype Induced by Maitake D-Fraction in Breast Cancer Cells

“…72 Recently, it has been identified that an NTdomain of SPARC and its 51-aa peptide are highly efficient in modulating and enhancing apoptosis, thereby conferring greater chemosensitivity to resistant tumors. 73 Also, it has been found that SPARC overexpression is a functionally important feature of a subset of triple-negative breast cancer patients. This study suggests that nab-paclitaxel may serve as a therapeutic agent for the subset of triple-negative patients that overexpress SPARC.…”

The Emerging Genetic Basis and Its Clinical Implication in Pancreatic Cancer

“…For example, to overcome the resistance mechanism related to the RAS/RAF/MEK/ERK pathway, several novel inhibitors including MEK inhibitors, BRAF inhibitors, HSP90 inhibitors, KRAS -directed immunotherapy, mTOR inhibitors and several combinations thereof have been tested [15]. An interplay between the N-terminus domain of secreted protein and rich in cysteine (SPARC), BCL2 and CASPASE-8 helps to augment apoptosis and consequently increase the response to treatment [105]. Combination treatment of gemcitabine and p53-reactivating molecules (CP-31398 and RITA) inhibits the proliferation of pancreatic cancer cells and induced apoptosis [16].…”