Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases
Open Access
- 8 January 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 26 (28), 4084-4094
- https://doi.org/10.1038/sj.onc.1210181
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.Keywords
This publication has 22 references indexed in Scilit:
- Albumin-bound paclitaxel: a next-generation taxaneExpert Opinion on Pharmacotherapy, 2006
- SPARC Regulates Extracellular Matrix Organization through Its Modulation of Integrin-linked Kinase ActivityJournal of Biological Chemistry, 2005
- Endogenous Osteonectin/SPARC/BM-40 Expression Inhibits MDA-MB-231 Breast Cancer Cell MetastasisCancer Research, 2005
- Secreted Protein Acidic and Rich in Cysteine Produced by Human Melanoma Cells Modulates Polymorphonuclear Leukocyte Recruitment and Antitumor Cytotoxic CapacityCancer Research, 2005
- SPARC and tumor growth: Where the seed meets the soil?Journal of Cellular Biochemistry, 2004
- Expression Profiling of Purified Normal Human Luminal and Myoepithelial Breast CellsCancer Research, 2004
- Cost of Migration: Invasion of Malignant Gliomas and Implications for TreatmentJournal of Clinical Oncology, 2003
- Cellular survival: a play in three AktsGenes & Development, 1999
- Assessment of brain tumor cell motility in vivo and in vitroJournal of Neurosurgery, 1995
- Measurement of blood-brain barrier permeability in a tumor model using magnetic resonance imaging with gadolinium-dtpaMagnetic Resonance in Medicine, 1992