Sensitivity and cellular response to different anticancer agents of a human ovarian cancer cell line expressing wild-type, mutated or no p53
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E A Graniela Sirè1, F Vikhanskaya, M Broggini
1Instituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Background:
The cytotoxicity and gene expression induced by anticancer drugs with different mechanisms of action was tested in clones from a human ovarian cancer cell line expressing no p53, mutated p53 or wild type (wt) p53.
Materials And Methods:
We used clones from SKOV3 cells transfected with a temperature-sensitive mutant p53 which expresses mutated p53 at 37 degrees C and a wild type-like p53 at 32 degrees C. Cytotoxicity and expression of p53-related genes (WAF1 and GADD45) were tested after 24 hours of treatment with different drugs.
Results:
All of the drugs were equally active in the different systems, independently of the presence of p53, with the exception of doxorubicin which was less cytotoxic in cells expressing a wtp53. An increase in the transcription of WAF1 and GADD45 genes was found in cells expressing p53 and treated with the drugs. GADD45 and WAF1 expression was also found in cells not expressing p53 but treated with the drugs, suggesting that these genes can also be activated by DNA damage through a pathway independent of p53. A highly DNA-sequence-specific alkylator, tallimustine (FCE 24517), which causes a very small number of DNA lesions, does not increase the expression of these genes. Cyclin D1 gene expression was not changed after treatment with the drugs tested in cells both expressing and not expressing wtp53.
Conclusions:
Our data suggest that p53 expression does not play a role in increasing the susceptibility of cells not undergoing apoptosis after DNA damage, but that, at least in the case of doxorubicin, it can enhance the repair systems and reduce the cytotoxicity.
Insights
p53 expression does not affect cancer cell susceptibility to DNA damage. However, it may enhance DNA repair mechanisms, reducing doxorubicin cytotoxicity in ovarian cancer cells.
Area of Science:
- Molecular biology
- Cancer research
- Genetics
Background:
- Investigated the role of p53 in cellular response to anticancer drugs.
- Utilized human ovarian cancer cell lines with varying p53 statuses (none, mutated, wild-type).
Purpose of the Study:
- To determine how p53 status influences cytotoxicity and gene expression induced by different anticancer drugs.
- To explore the role of p53 in DNA damage response pathways.
Main Methods:
- Employed SKOV3 cell clones with temperature-sensitive p53.
- Assessed cytotoxicity and expression of WAF1 and GADD45 genes after drug treatment.
- Tested various anticancer drugs with different mechanisms of action.
Main Results:
- Most drugs showed similar activity regardless of p53 status.
- Doxorubicin exhibited lower cytotoxicity in wild-type p53 cells.
- WAF1 and GADD45 gene expression increased in p53-expressing cells and also in p53-negative cells upon drug treatment, indicating p53-independent activation.
- Tallimustine did not alter WAF1/GADD45 expression.
- Cyclin D1 expression remained unchanged.
Conclusions:
- p53 status does not significantly impact cellular susceptibility to DNA damage-induced apoptosis.
- p53 may enhance DNA repair systems, reducing cytotoxicity, particularly for drugs like doxorubicin.