bims-midomi 2025-04-27 papers

Cells. 2025 Apr 12. pii: 583. [Epub ahead of print]14(8):

Strategies for p53 Activation and Targeted Inhibitors of the p53-Mdm2/MdmX Interaction.

Ye Huang, Wang Li, Yuke Zhou, Jinping Bai, Ning Li, Zhengding Su, Xiyao Cheng.

p53 is a tumor suppressor gene and is regarded as one of the most crucial genes in protecting humans against cancer. The protein Mdm2 and its homolog MdmX serve as negative regulators of p53. In nearly half of cancer cells, there is an overexpression of Mdm2 and MdmX, which inhibit p53 activity. Furthermore, Mdm2's E3 ubiquitin ligase activity promotes the ubiquitination and degradation of p53. Therefore, blocking the interaction between p53 and Mdm2/MdmX to prevent the degradation of wild-type p53 is an effective strategy for inhibiting tumor growth. This paper primarily discusses the regulatory relationship between p53, MdmX and Mdm2, and provides a review of the current status of p53-Mdm2/MdmX inhibitors. It aims to offer a theoretical foundation and research direction for the future discovery and design of targeted inhibitors against the p53-Mdm2/MdmX interaction.

Keywords: Mdm2; MdmX; cancer; inhibitors; p53

DOI: https://doi.org/10.3390/cells14080583

Biochim Biophys Acta Rev Cancer. 2025 Apr 19. pii: S0304-419X(25)00068-X. [Epub ahead of print]1880(3): 189326

The multifunctional proline-rich domain of p53 tumor suppressor.

Yuesheng Zhang, Madhuri Dutta.

The p53 tumor suppressor is a multi-domain protein. The proline-rich domain (PRD) resides next to the transactivation domains at the N-terminus and before the DNA binding domain. The PRD has been studied extensively for nearly three decades and has been shown to be a key component for the tumor suppressor functions of p53. However, study findings have not been analyzed systematically. Herein, we undertake a comprehensive review of the studies which examined the roles of the PRD in the biological functions, stability, and protein-protein interactions of p53. While p53 is one of the most frequently mutated cellular proteins in human cancer, mutation in its PRD is uncommon, which will be discussed. The importance of the PRD in regulation of mutant p53 has also been investigated and will be reviewed as well. In addition, one of the amino acids in the PRD in human p53 is polymorphic. Information about the polymorphism and its impact on p53 function and association with disease outcomes will also be reviewed. Collectively, studies to date demonstrate that the PRD is a multifunctional domain critical for a variety of p53 functions as well as p53 stability, and that the PRD polymorphism is a potential biomarker of cancer risk and cancer outcome. Its involvement in regulation of both wild-type and mutant p53 offers opportunities for potential development of novel cancer therapeutic strategies.

Keywords: Gene polymorphism; Proline-rich domain; TP53; Transcription-independent regulation; Transcriptional regulation; Tumor suppressor; p53

DOI: https://doi.org/10.1016/j.bbcan.2025.189326

Front Pharmacol. 2025 ;16 1508421

MDM2 inhibitor induces apoptosis in colon cancer cells through activation of the CHOP-DR5 pathway, independent of p53 phenotype.

Manman Lu, Yingli Ren, Sijia Feng, Shenggen Wang, Weiyue Xia, Baoru Gu, Yuhou Shen, Aimin Yue, Na Li, Yongxi Zhang, Jiateng Zhong.

Introduction: Murine double minute 2 (MDM2), a key negative regulator of p53, forms a feedback loop with p53 to drive tumor progression, including colorectal cancer. Nutlin-3a, an MDM2 inhibitor, induces apoptosis in wild-type p53 tumors, but its effects on p53-mutated cancers and potential p53-independent apoptotic mechanisms remain unclear.
Methods: We investigated Nutlin-3a's effects on colon cancer cells with varying p53 phenotypes. Endoplasmic reticulum (ER) stress-associated CHOP was detected and knocked down to explore mechanisms. In vitro and in vivo experiments assessed Nutlin-3a's synergy with 5-fluorouracil and TRAIL.
Results: Nutlin-3a activated caspase-8-dependent extrinsic apoptosis in colon cancer cells via DR5 upregulation, independent of p53 status. ER stress and CHOP activation mediated DR5 induction, driven by calcium release. Combined Nutlin-3a treatment enhanced sensitivity to 5-fluorouracil and TRAIL in vitro and in vivo through caspase-8 pathway activation.
Discussion: These findings reveal a novel p53-independent apoptotic mechanism of Nutlin-3a involving ER stress and death receptor signaling. This pathway highlights Nutlin-3a's potential as an adjuvant therapy for colon cancer, even in p53-mutated tumors, by enhancing chemotherapeutic efficacy through extrinsic apoptosis.

Keywords: ER stress; apoptosis; colorectal cancer; extrinsic apoptotic pathway; nutlin-3a

DOI: https://doi.org/10.3389/fphar.2025.1508421

Brief Funct Genomics. 2025 Jan 15. pii: elaf006. [Epub ahead of print]24

Integrative machine learning approach for identification of new molecular scaffold and prediction of inhibition responses in cancer cells using multi-omics data.

Aman Chandra Kaushik, Shubham Krushna Talware, Mohammad Imran Siddiqi.

MDM2 (Mouse Double Minute 2), a fundamental governor of the p53 tumor suppressor pathway, has garnered significant attention as a favorable target for cancer therapy. Recent years have witnessed the development and synthesis of potent MDM2 inhibitors. Despite the fact that numerous MDM2 inhibitors and degraders have been assessed in clinical studies for various human cancers, no FDA-approved drug targeting MDM2 is presently available in the market. Researchers have investigated the effects of various drugs, which are involved in cancer therapies with known mechanisms, on well-characterized cancer cell lines. The prediction of drug inhibition responses becomes crucial to enhance the effectiveness and personalization of cancer treatments. Such findings can provide new perceptions aimed at designing new drugs for targeted cancer therapies. In our current insilico work, a robust response was observed for Idasanutlin in cancer cell lines, indicating the drug's significant impact on gene expression. We also identified transcriptional response signatures, which were informative about the drug's mechanism of action and potential clinical application. Further, we applied a similarity search approach for the identification of potential lead compounds from the ChEMBL database and validated them by molecular docking and dynamics studies. The study highlights the potential of incorporating machine learning with omics and single-cell RNA-seq data for predicting drug responses in cancer cells. Our findings could provide valuable insights for improving cancer treatment in the future, particularly in developing effective therapies.

Keywords: Idasanutlin; cancer; machine learning; molecular scaffold; scRNA-Seq

DOI: https://doi.org/10.1093/bfgp/elaf006