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Published on: August 2, 2024
Cisplatin and PI3kinase inhibition decrease invasion and migration of human ovarian carcinoma cells and regulate
Amer K Karam1, Chintda Santiskulvong, Mirela Fekete
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. akaram@mednet.ucla.edu
Abstract:
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.
Insights
Targeting the PI3K/Akt/mTOR pathway with cisplatin and LY294002 significantly reduced ovarian cancer cell invasion and migration. This was linked to decreased expression of matrix metalloproteinases (MMPs) and their inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key regulator of cell growth and survival.
- Aberrant PI3K/Akt/mTOR signaling is implicated in various cancers, including ovarian cancer.
- Targeting this pathway represents a promising therapeutic strategy for ovarian cancer.
Purpose of the Study:
- To investigate the effects of cisplatin and the PI3K inhibitor LY294002 on ovarian cancer cell invasion and migration.
- To examine the impact of these treatments on the expression of matrix metalloproteinases (MMPs) and their inhibitors.
Main Methods:
- Utilized three human ovarian cancer cell lines (SKOV3, OVCAR5, IGROV1).
- Treated cells with cisplatin, LY294002, or a combination of both drugs.
- Assessed cell invasion and migration using Matrigel and PET membrane assays.
- Quantified MMP and TIMP expression via Western Blotting and gel zymography.
Main Results:
- Cisplatin, LY294002, and their combination significantly reduced ovarian cancer cell invasion and migration.
- Treatments led to a marked decrease in activated matrix metalloproteinase-2 (MMP2) levels in SKOV3 cells.
- Expression of tissue inhibitor of metalloproteinase-1 (TIMP1) and TIMP2 was significantly downregulated by the treatments, particularly the combination therapy.
- Matrix metalloproteinase MT1-MMP expression remained unchanged.
Conclusions:
- Inhibition of the PI3K/Akt/mTOR pathway, combined with cisplatin, effectively reduces ovarian cancer cell motility.
- The observed anti-motility effects are associated with the downregulation of activated MMP2, TIMP1, and TIMP2.
- These findings support the therapeutic potential of targeting the PI3K/Akt/mTOR pathway in ovarian cancer treatment.
