A peptide of sparc interferes with the interaction between Caspase8 and Bcl2 to resensitize Chemoresistant tumors and enhance their regression in vivo

Mahbuba Rahman, Annie P K Chan, Isabella T. Tai

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Article numbere26390
JournalPLoS One
Volume6
Issue number11
DOIs
Publication statusPublished - 1 Nov 2011
Externally publishedYes

Fingerprint

Tumors
peptides
Chemotherapy
Peptides
neoplasms
caspase-8
drug therapy
Caspase 8
apoptosis
Neoplasms
Apoptosis
Drug Therapy
Cells
Genes
follistatin
Follistatin
Tumor Suppressor Proteins
pancreatic neoplasms
therapeutics
remission

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A peptide of sparc interferes with the interaction between Caspase8 and Bcl2 to resensitize Chemoresistant tumors and enhance their regression in vivo. / Rahman, Mahbuba; Chan, Annie P K; Tai, Isabella T.

In: PLoS One, Vol. 6, No. 11, e26390, 01.11.2011.

Research output: Contribution to journalArticle

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