Secreted Protein Acidic, Rich in Cysteine (SPARC), Mediates Cellular Survival of Gliomas through AKT Activation

Abstract

Secreted protein acidic, rich in cysteine (SPARC), is an extracellular matrix protein expressed in many advanced cancers, including malignant gliomas. We and others have previously shown that human glioma cell lines engineered to overexpress SPARC adopt an invasive phenotype. We now show that SPARC expression increases cell survival under stress initiated by serum withdrawal through a decrease in apoptosis. Phosphatidylinositol 3-OH kinase/AKT is a potent pro-survival pathway that contributes to the malignancy of gliomas. Cells expressing SPARC display increased AKT activation with decreased caspase 3/7 activity. Exogenous SPARC rapidly induces AKT phosphorylation, an effect that is blocked by a neutralizing SPARC antibody. Furthermore, AKT activation is essential for the anti-apoptotic effects of SPARC as the decreased apoptosis and caspase activity associated with SPARC expression can be blocked with dominant-negative AKT or a specific AKT inhibitor. As tumor cells face stressful microenvironments particularly during the process of invasion, these results suggest that SPARC functions, in part, to promote tumor progression by enabling tumor cells to survive under stressful conditions.

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

“…Our laboratory previously demonstrated that SPARC activates the phosphoinositide-3-kinase-AKT pathway, a key mediator of cellular survival (Shi et al, 2004). Therefore, we first determined whether SPARC siRNA could alter AKT phosphorylation at key residues reflecting kinase activation.…”

“…Thus, SPARC siRNA can decrease glioma invasion in vitro. SPARC siRNA inhibits the survival of glioma cells As our laboratory previously demonstrated that overexpression of SPARC in glioma cell lines promotes survival under serum starvation (Shi et al, 2004), we investigated whether SPARC siRNA could decrease the survival of glioma cells under this stress. D54MG and U373MG glioma cells transfected with SPARC siRNA survived at decreased rates relative to matched cells transfected with a non-targeting control siRNA ( Figure 2).…”

“…However, in human glioma cell lines, SPARC increases invasion in vitro and in vivo (Schultz et al, 2002;Rich et al, 2003). SPARC also promotes cell survival through the activation of AKT/protein kinase B (Shi et al, 2004), an intracellular serine/threonine kinase known to inhibit apoptosis and known to be activated in cancer (Datta et al, 1999). We recently demonstrated that exogenous SPARC protein induces activating phosphorylation of AKT within minutes in a concentration-dependent manner, and stable overexpression of SPARC also increases AKT phosphorylation (Shi et al, 2004).…”

“…SPARC also promotes cell survival through the activation of AKT/protein kinase B (Shi et al, 2004), an intracellular serine/threonine kinase known to inhibit apoptosis and known to be activated in cancer (Datta et al, 1999). We recently demonstrated that exogenous SPARC protein induces activating phosphorylation of AKT within minutes in a concentration-dependent manner, and stable overexpression of SPARC also increases AKT phosphorylation (Shi et al, 2004). Therefore, we hypothesized that, in gliomas, decreasing SPARC expression could reduce AKT phosphorylation to decrease invasion and increase cell death.…”

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

“…These proteins, usually referred as matricellular proteins, though not being structurally related, regulate similar biological functions during embryonic development, tissue injury and cancer development mainly by promoting adhesion, migration and survival of cells (Bornstein and Sage, 2002). While absent in almost all normal healthy adult tissues, expression of SPARC for example is restored in many cancer types (Framson and Sage, 2004) and it has been demonstrated that SPARC overexpression is correlated with an increase in invasiveness and survival of cancer cells (Rich et al, 2003;Shi et al, 2004). Therefore, based on the important similarities between SPARC and periostin in terms of expression in the desmoplastic tumoral stroma and their common stimulatory effects on the invasion and survival of tumour cells, our results suggest that periostin could act in a similar manner as other matricellular proteins by facilitating the development and progression of pancreatic cancer.…”