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p73 cooperates with DNA damage agents to induce apoptosis in MCF7 cells in a p53-dependent manner
1Institute of Molecular Medicine and Genetics Medical College of Georgia, Augusta, Georgia, GA 30912, USA.
Abstract:
p73, a member of the p53 family, can induce apoptosis in cancer cells. Since p53-mediated apoptosis can be augmented by various cancer chemotherapeutic agents, it has been hypothesized that the status of the endogenous p53 gene in cancer cells is a key determinant in the outcome of cancer therapy. To determine whether p73 can sensitize cancer cells to apoptosis by DNA damage agents, several MCF7 adenocarcinoma cell lines that inducibly express p73 or p53 under a tetracycline-regulated promoter were generated. We found that at relevant physiological levels, p73, but not p53, is capable of sensitizing MCF7 cells to apoptosis induced by chemotherapeutic agents. In addition, we found that p73 can cooperate with the DNA damaging agent camptothecin to activate the initiator caspase 2. Furthermore, we found that p73 can cooperate with DNA damaging agents or p53 to induce some p53 target genes and activate their promoters. In contrast, in MCF7E6 cells that ectopically express the human papillomavirus E6 oncogene and are functionally p53-null, the ability of p73 to sensitize cells to apoptosis is abrogated. Taken together, these results suggest that a functional interaction between p53 and p73 in MCF7 cells leads to enhanced induction of apoptosis.
Insights
The p73 protein sensitizes cancer cells to chemotherapy-induced apoptosis, particularly when interacting with p53. This interaction enhances apoptosis induction, offering potential therapeutic strategies for cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Death Mechanisms
Background:
- The p53 protein is crucial in cancer therapy, as its apoptosis-inducing function can be enhanced by chemotherapeutic agents.
- The role of p73, a p53 family member, in sensitizing cancer cells to apoptosis, especially in conjunction with DNA-damaging agents, requires further elucidation.
Purpose of the Study:
- To investigate whether the p73 protein can sensitize cancer cells to apoptosis induced by DNA-damaging chemotherapeutic agents.
- To explore the cooperative mechanisms between p73, p53, and DNA-damaging agents in inducing cancer cell death.
Main Methods:
- Generation of MCF7 adenocarcinoma cell lines with inducible expression of p73 or p53 using a tetracycline-regulated promoter.
- Treatment of cell lines with chemotherapeutic agents and DNA-damaging agents (e.g., camptothecin).
- Assessment of apoptosis induction, caspase 2 activation, and p53 target gene promoter activity.
Main Results:
- At physiological levels, p73, but not p53, sensitized MCF7 cells to apoptosis induced by chemotherapeutic agents.
- p73 cooperated with camptothecin to activate caspase 2 and with DNA-damaging agents or p53 to induce p53 target genes.
- The ability of p73 to sensitize cells to apoptosis was abrogated in MCF7E6 cells expressing the human papillomavirus E6 oncogene (p53-null).
Conclusions:
- A functional interaction between p53 and p73 in MCF7 cells enhances apoptosis induction.
- p73 plays a significant role in sensitizing cancer cells to DNA damage-induced apoptosis, potentially through caspase 2 activation and cooperation with p53.
- These findings suggest that targeting p73 and its interaction with p53 could be a viable strategy in cancer therapy.