Cisplatin and PI3kinase inhibition decrease invasion and migration of human ovarian carcinoma cells and regulate matrix-metalloproteinase expression
| Autor: | Sara Zabih, Amer Karam, Oliver Dorigo, Mirela Fekete, Carol Eng, Chintda Santiskulvong |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cell Survival
Morpholines Protein Serine-Threonine Kinases Biology Article Phosphatidylinositol 3-Kinases Cell Movement Structural Biology Cell Line Tumor Ovarian carcinoma medicine Humans Phosphorylation PI3K/AKT/mTOR pathway Cell Proliferation Phosphoinositide-3 Kinase Inhibitors TIMP1 Ovarian Neoplasms Cisplatin Tissue Inhibitor of Metalloproteinase-2 Matrigel Tissue Inhibitor of Metalloproteinase-1 Cell growth TOR Serine-Threonine Kinases Intracellular Signaling Peptides and Proteins Cell Biology medicine.disease Molecular biology Enzyme Activation Chromones Cell culture Cancer research Matrix Metalloproteinase 2 Female Ovarian cancer Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Cytoskeleton. |
| ISSN: | 1949-3592 1949-3584 |
| DOI: | 10.1002/cm.20465 |
| Popis: | Targeting of the PI3K (phosphoinositide3-kinase)/Akt/mTOR pathway in human ovarian cancer cells is a promising novel therapeutic strategy. We investigated the effects of cisplatin and the PI3K inhibitor LY294002 on invasion, migration and the expression of essential matrix metalloproteinases (MMPs) in ovarian cancer cells. SKOV3, OVCAR5 and IGROV1 human ovarian cancer cell lines were treated with cisplatin, LY294002 and a combination of both drugs. Invasion and migration of treated cells was assessed using Matrigel and uncoated PET membrane assays. Expression levels of pro-MMP2, MMP2, TIMP1, TIMP2 and MT1-MMP were determined using Western Blotting. Gel zymography was used to quantitate the functional levels of active MMP2. All three cell lines showed significantly reduced invasion and migration after treatment with cisplatin, LY294002, and the combination of both drugs compared to untreated controls. In SKOV3 cells, cisplatin alone and in combination with LY294002 resulted in a 6.3 and 7.1-fold reduction in the total amount of activated MMP2. TIMP1 expression decreased by 5.0, 6.6 and 28.4-fold with cisplatin, LY294002 and the combination respectively (P < 0.05). In contrast, only cisplatin and the combination of both drugs resulted in a significant, 3.7 and 5.1-fold reduction in the level of TIMP2. Expression levels of MT1-MMP remained unchanged. These observations were corroborated in IGROV1 cell lines that showed similar changes of activated MMP2 and TIMP2 expression, but no significant decrease in TIMP1 levels. Our data suggests that inhibition of ovarian cancer cell motility is mediated via down-regulation of activated MMP2, TIMP1 and TIMP2 expression under these treatment conditions. |
| Databáze: | OpenAIRE |
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