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Pharmacological targeting of p53 pathway alterations in tumors

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posted on 2024-09-03, 06:12 authored by Ying Zhao

The p53 tumor suppressor plays an important role in cell fate decisions upon diverse stress conditions. In response to stress, p53 functions as a transcription factor, activating transcription of a variety of its target genes responsible for several cellular responses, most importantly cell cycle arrest and apoptosis. The p53 gene is one of the most frequently mutated genes in cancer. Dysfunction of the p53 protein due to gene mutations has been observed in ca 50% of all known human cancers. In the other half of human tumors, p53 is not functional due to extensive degradation by MDM2 or HPVE6/E6AP. Inactivation of p53 is essential for tumor survival, therefore the strategy aimed at restoring its functions is a promising approach for cancer treatment.

Previously identified small molecule RITA has been shown to rescue p53 functions in tumor cells where it protects p53 from MDM2-mediated degradation. RITA reactivates p53 and triggers apoptosis in tumor cells while it does not affect normal cells. Here, we address the questions whether RITA can rescue p53 function upon its inactivation in HPV-E6 and point mutations in the p53 gene.

Cervical cancer is one of the most common cancer types in women worldwide. It is causally linked to infection by the human papilloma virus whose E6 oncoprotein hijacks a cellular E3 ligase, E6AP (E6-associated protein), and targets p53 for degradation. Here, we show that RITA can reduce the interaction between p53 and E6AP, thereby reactivating p53 in cervical carcinoma cells. RITA rescued p53 s transcriptional functions and induced apoptosis in a p53-dependent manner. Importantly, RITA suppressed growth of cervical carcinoma xenografts in vivo.

We found that small molecule RITA rescued the function of various p53 mutants in tumor cell lines of different origin. RITA triggered p53-dependent growth suppression in cells that harbor mutant p53 and induced apoptosis. Similar to its effects in wild-type p53 expressing cells, RITA restored mutant p53 s transcriptional activity. Thus, RITA can rescue the function of both wild-type and mutant p53.

Notably, we found that 53BP1, an important mediator of DNA damage response, plays a critical role in the tumor-specific effects of RITA. Furthermore, we found that 53BP1 interacts with and stabilizes both wild-type and mutant p53 in tumor cells. 53BP1 regulates p53 stability upon DNA damage or oncogenic stress but not in untransformed cells. This suggests that 53BP1 confers tumor-selective p53 stabilization. However, depending on the p53 status, 53BP1 might function as an tumor suppressor in cells with wild-type p53, or as an oncogene when it stabilizes mutant p53.

In conclusion, our findings show that RITA has specificity towards tumor cells expressing wild-type or mutant p53, and can serve as a lead compound for future development of target-specific anti-cancer drugs.

List of scientific papers

I. Zhao CY, Szekely L, Bao W, Selivanova G (2010). "Rescue of p53 function by small-molecule RITA in cervical carcinoma by blocking E6-mediated degradation." Cancer Res 70(8): 3372-81.
https://doi.org/10.1158/0008-5472.CAN-09-2787

II. Zhao Y, Grinkevich VV, Nikulenkov F, Bao W, Selivanova, G (2010). "Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA." Cell Cycle. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/20436301

III. Bao W, Nikulenkov F, Zhao Y, Spinnler C, Bartek J, Selivanova G (2010). "Crucial role f 53BP1 in the stabilization of wild-type and mutant p53 upon oncogene activation." [Manuscript]

History

Defence date

2010-06-17

Department

  • Department of Microbiology, Tumor and Cell Biology

Publication year

2010

Thesis type

  • Doctoral thesis

ISBN

978-91-7409-973-7

Number of supporting papers

3

Language

  • eng

Original publication date

2010-05-27

Author name in thesis

Zhao, Ying

Original department name

Department of Microbiology, Tumor and Cell Biology

Place of publication

Stockholm

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