Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation.
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.
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Qing
Q
Shi
Shideng
S
Bao
Jill A
JA
Maxwell
Elizabeth D
ED
Reese
Henry S
HS
Friedman
Darell D
DD
Bigner
Xiao-Fan
XF
Wang
Jeremy N
JN
Rich
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D005910:Glioma / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D015676:Osteonectin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology
D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D016895:Culture Media, Serum-Free; D015676:Osteonectin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; C494918:AKT1 protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human