Tumor-specific induction of apoptosis by a p53-reactivating compound
Elisabeth Hedström1, Natalia Issaeva, Martin Enge
1The Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, SE-171 77, Stockholm, Sweden.
Abstract:
The tumor suppressor function of p53 is disabled in the majority of tumors, either by a point mutation of the p53 gene, or via MDM2-dependent proteasomal degradation. We have screened a chemical library using a cell-based assay and identified a low molecular weight compound named MITA which induced wild-type p53-dependent cell death in a variety of different types of human tumor cells, such as lung, colon and breast carcinoma cells, as well as in osteosarcoma and fibrosarcoma-derived cells. MITA inhibited p53-MDM2 interaction in vitro and in cells, which in turn prevented MDM2-mediated ubiquitination of p53 and resulted in a prolonged half-life and accumulation of p53 in tumor cells. Notably, p53 induction by MITA resulted in upregulated expression of p53 target genes MDM2, Bax, Gadd45 and PUMA, on protein and mRNA level. Importantly, neither p53 nor these target genes were induced in normal human fibroblasts (HDFs), which correlated with the absence of growth suppression in fibroblasts after treatment with MITA. However, upon activation of oncogenes in fibroblasts an induction and activation of p53 was observed, suggesting that activation of p53 by MITA occurs predominantly in tumor cells.
Insights
A new compound, MITA, reactivates the tumor suppressor p53 in cancer cells by inhibiting p53-MDM2 interaction. This leads to cancer cell death, while sparing normal cells, offering a potential new cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The tumor suppressor p53 is crucial for preventing cancer but is often inactivated in tumors through mutation or MDM2-mediated degradation.
- Targeting p53 reactivation is a promising strategy for cancer treatment.
Purpose of the Study:
- To identify novel compounds that can restore wild-type p53 tumor suppressor function in cancer cells.
- To investigate the mechanism of action of such compounds.
Main Methods:
- A cell-based chemical library screen was employed to identify compounds inducing p53-dependent cell death.
- In vitro and cellular assays were used to assess MITA's effect on p53-MDM2 interaction, p53 ubiquitination, and p53 target gene expression.
- Experiments were conducted in various human tumor cell lines and normal human fibroblasts (HDFs).
Main Results:
- MITA, a low molecular weight compound, selectively induced cell death in multiple human tumor cell types.
- MITA inhibited the interaction between p53 and MDM2, preventing p53 ubiquitination and increasing p53 levels.
- MITA upregulated key p53 target genes (MDM2, Bax, Gadd45, PUMA) at the protein and mRNA levels in tumor cells.
- MITA did not induce p53 or target gene expression in normal HDFs, indicating tumor cell specificity.
- p53 activation by MITA was observed in HDFs only upon oncogene activation, suggesting a tumor-predominant effect.
Conclusions:
- MITA effectively reactivates wild-type p53 tumor suppressor activity selectively in cancer cells.
- MITA's mechanism involves disrupting the p53-MDM2 interaction, leading to p53 stabilization and apoptosis induction in tumors.
- MITA represents a potential therapeutic agent for cancers with functional wild-type p53.
Related Concept Videos
02:23Abnormal Proliferation
01:31The Intrinsic Apoptotic Pathway
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:27Tumor Immunotherapy
02:36DNA Damage can Stall the Cell Cycle