SPARC (Secreted Protein Acidic and Rich in Cysteine) Induces Apoptosis in Ovarian Cancer Cells

Abstract

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular Ca(2+)-binding matricellular glycoprotein that associates with cell populations undergoing migration, morphogenesis, and differentiation. Studies on endothelial cells have established that its principal functions in vitro are counteradhesion and antiproliferation. The mechanism(s) underlying these antitumor effects is unknown. In this study, we showed that SPARC expression in ovarian cancer cells is inversely correlated with the degree of malignancy. The immunohistochemical data presented here confirmed the importance of diminished SPARC expression in ovarian cancer development. Treating human ovarian surface epithelial cells and ovarian cancer cells with SPARC revealed that as SPARC inhibits the proliferation of both normal and cancer cells, it induces apoptosis only in cancer cells. This observation indicates that down-regulation of SPARC is essential for ovarian carcinogenesis as cancer cells become sensitized to the apoptotic activity of SPARC during malignant transformation. We also showed here the first direct evidence that putative SPARC receptors are present on ovarian epithelial cells. Their levels are higher in human ovarian surface epithelial cells than cancer cells. Binding of SPARC to its receptor is likely to trigger tissue-specific signaling pathways that mediate its tumor suppressing functions. Decrease in ligand-receptor interaction by the down-regulation of SPARC and/or its receptor is essential for ovarian carcinogenesis.

Characterisation of human kallikrein 6/protease M expression in ovarian cancer

“…The specificity of the staining was confirmed by preabsorbing the antibody with the purified hK6 protein for 2 h at 371C before applying to the sections. The results of immunohistochemistry were quantified using a semiquantitative scoring system (Yiu et al, 2001). The weighted score is obtained by multiplying the staining intensity score (3 þ , strong positive stain in most cells; 2 þ , moderate stain in cells; 1 þ , weak stain in cells; 0, no evidence of stain) and score for the percentage of positive cells (3 þ , most of cells stained; 2 þ , half of cells stained; 1 þ , few cells stained; 0, no cells stained).…”

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

“…However, as SPARC has the potential to function both as a tumor promoter and tumor suppressor, decreasing SPARC expression may not be beneficial for all tumor types or stages. For example, SPARC induces apoptosis in ovarian cancer cells (Yiu et al, 2001) and inhibits proliferation and metastasis of breast cancer cells (Koblinski et al, 2005), but breast tumor expression of SPARC is linked to increased patient metastases and poor patient survival (Jones et al, 2004;Watkins et al, 2005). When we overexpressed SPARC in HeLa cells or a genetically engineered human breast cancer model (HMEC), SPARC-expressing cells suffered a dramatic inhibition of tumor formation when implanted into immunocompromised rodents (data not shown).…”

A Conserved Organization of Transcription during Embryonic Stem Cell Differentiation and in Cells with High C Value

“…Oct-4 (also known as Oct-3/4) is a marker for pluripotency and a member of the Pit1-Oct1-Unc86 family of transcription factors; it is required for stem cell self-renewal and is lost when ES cells differentiate (Niwa et al, 2000). Conversely, SPARC is a calcium-binding matricellular glycoprotein and a specific marker for parietal endoderm (Mason et al, 1986;Nomura et al, 1988;Yiu et al, 2001).…”

“…Oct-4 (also known as Oct-3/4) is a marker for pluripotency and a member of the Pit1-Oct1-Unc86 family of transcription factors; it is required for stem cell self-renewal and is lost when ES cells differentiate (Niwa et al, 2000). Conversely, SPARC is a calcium-binding matricellular glycoprotein and a specific marker for parietal endoderm (Mason et al, 1986;Nomura et al, 1988;Yiu et al, 2001).F9 cells differentiate on addition of retinoic acid, dibutyryl cyclical AMP, and 3-isobutyl-1-methylxanthine (hereafter this treatment is called RA; Strickland and Mahdavi, 1978;Strickland et al, 1980;Gardner, 1983;Hogan et al, 1983). About 70% of the population become individual and migratory, losing Oct-4 and gaining SPARC ( Figure 1A; our unpublished data); this is typical of parietal endoderm.…”