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Published on: May 20, 2014
Resistance to p53-mediated growth suppression in human ovarian cancer cells retain endogenous wild-type p53
1Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0936, USA.
Abstract:
Cancer cells containing mutated p53 are sensitive to the re-introduction of the wild-type (wt) p53. We sought to determine whether ovarian cancer cells that retain wt p53 are sensitive to the re-introduction of wt p53. Our results demonstrated that A2780 and PA-1 cells, which retain wt p53, are more resistant to apoptosis and growth suppression induced by exogenous expression of wt p53 than SKOV-3 and Caov-3 cells that contain mutated p53. All cell lines, except PA-1, showed induction of the p53-targeted genes. Further, inhibitors of p53-dependent apoptosis, mdm2 and Bcl-xL were not overexpressed in A2780 and PA-1 cells. These results suggest that one major defect in PA-1 cells is due to abrogation of induction of the p53-targets which is independent of mdm2 and Bcl-xL. Although A2780 cells showed induction of the p53-targeted genes, the cleavage of caspase-9 was undetectable. Therefore, p53-dependent apoptosis may be blocked upstream or at the caspase-9 level in A2780 cells.
Insights
Ovarian cancer cells with wild-type p53 show resistance to p53 reintroduction, unlike those with mutated p53. This resistance is linked to defects in p53-targeted gene induction and apoptosis pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Mutated p53 is a common event in many cancers, and its wild-type (wt) counterpart can suppress tumor growth.
- Reintroducing wt p53 into cancer cells with mutated p53 can induce apoptosis and inhibit proliferation.
- The sensitivity of ovarian cancer cells retaining wt p53 to exogenous wt p53 reintroduction remains largely unexplored.
Purpose of the Study:
- To investigate the response of ovarian cancer cells with wild-type p53 to the reintroduction of exogenous wild-type p53.
- To compare the sensitivity of ovarian cancer cells with wild-type p53 versus mutated p53 to wt p53 expression.
- To identify potential mechanisms underlying resistance or sensitivity to wt p53 reintroduction in ovarian cancer cells.
Main Methods:
- Ovarian cancer cell lines (A2780, PA-1, SKOV-3, Caov-3) were utilized, characterized by their p53 mutational status (wt or mutated).
- Exogenous expression of wild-type p53 was achieved in these cell lines.
- Apoptosis, cell growth suppression, p53-targeted gene induction, and expression of apoptosis inhibitors (mdm2, Bcl-xL) were assessed.
Main Results:
- Ovarian cancer cells retaining wt p53 (A2780, PA-1) exhibited greater resistance to apoptosis and growth suppression upon exogenous wt p53 expression compared to cells with mutated p53 (SKOV-3, Caov-3).
- Most cell lines, except PA-1, demonstrated induction of p53-targeted genes following wt p53 reintroduction.
- Inhibitors of p53-dependent apoptosis, mdm2 and Bcl-xL, were not overexpressed in the resistant A2780 and PA-1 cells.
- Cleavage of caspase-9 was undetectable in A2780 cells, suggesting a block in the p53-dependent apoptosis pathway at or upstream of caspase-9.
Conclusions:
- Ovarian cancer cells with wild-type p53 are generally resistant to the pro-apoptotic and anti-proliferative effects of exogenous wt p53 reintroduction.
- Resistance in PA-1 cells is associated with an abrogation of p53-target gene induction, independent of mdm2 and Bcl-xL.
- In A2780 cells, p53-dependent apoptosis appears to be blocked at the caspase-9 level or upstream, despite successful induction of p53-targeted genes.
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