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p53: prospects for cancer gene therapy
1Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, CRS, Rome, Italy.
Abstract:
Initially described as an oncogene, at the end of the 1980s, the wild-type p53 gene (TP53) was later shown to be capable of suppressing the proliferation of transformed cells. In the following years, an increasing number of studies demonstrated that intact p53 function is essential for the maintenance of the non-tumorigenic phenotype of cells. Indeed, functional inactivation of the p53 protein is one of the most common alterations observed in human cancers. More recently, it has been shown that inactivation of the TP53 tumor suppressor gene may lead to radioresistant and chemoresistant tumors, possibly by the induction of apoptosis-resistant phenotypes. Finally, a large number of in vitro and in vivo transduction experiments have demonstrated that exogenous TP53 overexpression can suppress the transformed phenotype of many cell types by inducing growth arrest, apoptosis or cell differentiation. All of these findings have rendered p53 a potentially helpful target for the therapy of many types of human cancers. In this review we shall discuss the different approaches to p53-related cancer therapy that have been proposed on the basis of this large number of experimental studies, and we shall try to dissect the biological questions that are still open and need to be clarified to improve p53-based therapy.
Insights
The wild-type p53 gene (TP53) suppresses tumors, but its inactivation is common in human cancers, leading to resistance. Restoring p53 function offers a promising strategy for cancer therapy.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The p53 gene (TP53) initially identified as an oncogene, was later recognized for its tumor-suppressive functions.
- Functional inactivation of p53 is a frequent event in human cancers, contributing to tumor development and progression.
- Loss of p53 function is linked to radioresistance and chemoresistance, often through apoptosis-resistant phenotypes.
Purpose of the Study:
- To review current p53-based cancer therapeutic strategies.
- To discuss the biological questions that need clarification for improved p53-based therapies.
- To highlight the potential of targeting p53 for cancer treatment.
Main Methods:
- Review of in vitro and in vivo experimental studies.
- Analysis of transduction experiments demonstrating exogenous TP53 overexpression.
- Discussion of therapeutic approaches based on experimental findings.
Main Results:
- Wild-type p53 suppresses cell proliferation and transformation.
- Exogenous TP53 overexpression can induce growth arrest, apoptosis, or differentiation, suppressing the transformed phenotype.
- Inactivation of TP53 contributes to radioresistant and chemoresistant tumors.
Conclusions:
- p53 is a crucial tumor suppressor, essential for maintaining the non-tumorigenic phenotype.
- Restoring or exploiting p53 function presents a viable therapeutic avenue for various human cancers.
- Further research is needed to optimize p53-based cancer therapies.