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Differential susceptibility to etoposide in clones derived from a human ovarian cancer cell line
K V Balan1, N M Sitaras, K Dimas
1Department of Biology, University of Miami, Coral Gables, FL 33146, USA.
Objectives:
To identify parameters/factors that may contribute to the differential sensitivity to etoposide in two clones isolated from the human ovarian carcinoma SKOV-3 cell line, which does not express p53 and is resistant to platinum-based regimens.
Methods:
Differential sensitivity of the cells to etoposide was monitored by microscopy to observe morphological changes, by flow cytometry analyses to detect cell cycle perturbations, and by molecular/biochemical assays to identify events involved in induction of apoptosis.
Results:
Etoposide treatment (1) induced apoptosis in one clone, ES, but not in another clone, ER, (2) had no effect on the expression of the antiapoptotic proteins Bcl-2 and Bcl-X(L) in both cell clones, whereas the proapoptotic proteins Bak and Bax were dramatically upregulated in ES, but not ER cells, and (3) induced more extensive processing of procaspase-8, procaspase-9, and the caspase-3-targeted substrates, topoisomerase I and PARP, in ES cells. Ectopic overexpression of Bcl-2 in ES cells failed to inhibit etoposide-induced apoptosis.
Conclusions:
The differential susceptibility of ES and ER cells to etoposide-induced apoptosis is associated with differences in several events rather than with a specific single genetic regulator of the apoptotic machinery. We propose that the differential response of ovarian cancer patients to etoposide treatment is associated with the number of etoposide-sensitive cells in the tumor.
Insights
This study investigated why some ovarian cancer cells are more sensitive to etoposide than others. Researchers found differences in apoptosis-related protein activity, not a single gene, determine etoposide sensitivity in SKOV-3 cell clones.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Ovarian cancer SKOV-3 cell line is p53-null and platinum-resistant.
- Understanding etoposide sensitivity is crucial for ovarian cancer treatment.
Purpose of the Study:
- Identify factors contributing to differential etoposide sensitivity in two SKOV-3 cell clones (ES and ER).
- Investigate the molecular mechanisms underlying etoposide-induced apoptosis in these clones.
Main Methods:
- Microscopy for morphological changes.
- Flow cytometry for cell cycle analysis.
- Molecular assays for apoptosis-related protein expression and caspase activation.
Main Results:
- Etoposide induced apoptosis in ES cells but not ER cells.
- Proapoptotic proteins Bak and Bax were upregulated in ES cells.
- Extensive caspase processing occurred in ES cells, indicating apoptosis induction.
Conclusions:
- Differential etoposide sensitivity is linked to multiple apoptotic events, not a single regulator.
- Patient response to etoposide may correlate with the proportion of sensitive tumor cells.
