bims-midomi 2025-08-03 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–08–03
six papers selected by
Gavin McStay, Liverpool John Moores University

Regulation of the MDM2-p53 Nexus by a Nuclear Phosphoinositide and Small Heat Shock Protein Complex.
Selective Cleaning Enhances Machine Learning Accuracy for Drug Repurposing: Multiscale Discovery of MDM2 Inhibitors.
Molecular profile and clinical impact of MDM2 amplification in patients with advanced biliary tract cancer.
Dihydroartemisinin inhibits NSCLC by targeting MDM2/c-Myc axis independent of p53.
Uncovering dual oscillatory regimes in p53-mdm2 dynamics: A data-driven modeling approach with implications for cancer progression.
HDM-2-Targeting Peptide PNC-27 Kills Cervical Cancer Cells but not Normal Cervical Cells.

J Biol Chem. 2025 Jul 26. pii: S0021-9258(25)02378-6. [Epub ahead of print] 110527

Regulation of the MDM2-p53 Nexus by a Nuclear Phosphoinositide and Small Heat Shock Protein Complex.

Jeong Hyo Lee, Mo Chen, Tianmu Wen, Richard A Anderson, Vincent L Cryns.

  The tumor suppressor p53 maintains genome stability in the setting of cellular stress and is frequently mutated in cancer. The stability of p53 is regulated by its interaction with the oncoprotein MDM2, a ubiquitin E3 ligase. Recently, nuclear phosphoinositides were reported to bind and stabilize p53. Here, we report that genotoxic stress induces the type I phosphatidylinositol phosphate kinase (PIPKIα) and its product phosphatidylinositol 4,5-bisphosphate (PIP2) to bind and regulate the stability and function of MDM2. Following genotoxic stress, nuclear PIPKIα binds to MDM2 to generate a complex of MDM2 and PIP2. PIP2 binding to MDM2 differentially regulates the recruitment of the small heat shock proteins (sHSPs) αB-crystallin (αBC) and HSP27 to the MDM2-PIP2 complex, acting as an on-off switch that regulates MDM2 stability, ubiquitination activity and interaction with p53. Our results demonstrate an unexpected role for nuclear phosphoinositides conferring specificity to the MDM2-PIP2-sHSPs association. Notably, the differential engagement of αBC and HSP27 reveals that sHSPs are not merely passive chaperones but play active, selective roles in fine-tuning MDM2 function and the MDM2-p53 nexus. These findings provide a previously unrecognized molecular framework for targeting this pathway in cancer.

Keywords:  MDM2; Nucleus; PIP(2); Small heat shock protein; p53

DOI:  https://doi.org/10.1016/j.jbc.2025.110527
Molecules. 2025 Jul 16. pii: 2992. [Epub ahead of print]30(14):

Selective Cleaning Enhances Machine Learning Accuracy for Drug Repurposing: Multiscale Discovery of MDM2 Inhibitors.

Mohammad Firdaus Akmal, Ming Wah Wong.

  Cancer remains one of the most formidable challenges to human health; hence, developing effective treatments is critical for saving lives. An important strategy involves reactivating tumor suppressor genes, particularly p53, by targeting their negative regulator MDM2, which is essential in promoting cell cycle arrest and apoptosis. Leveraging a drug repurposing approach, we screened over 24,000 clinically tested molecules to identify new MDM2 inhibitors. A key innovation of this work is the development and application of a selective cleaning algorithm that systematically filters assay data to mitigate noise and inconsistencies inherent in large-scale bioactivity datasets. This approach significantly improved the predictive accuracy of our machine learning model for pIC50 values, reducing RMSE by 21.6% and achieving state-of-the-art performance (R2 = 0.87)-a substantial improvement over standard data preprocessing pipelines. The optimized model was integrated with structure-based virtual screening via molecular docking to prioritize repurposing candidate compounds. We identified two clinical CB1 antagonists, MePPEP and otenabant, and the statin drug atorvastatin as promising repurposing candidates based on their high predicted potency and binding affinity toward MDM2. Interactions with the related proteins MDM4 and BCL2 suggest these compounds may enhance p53 restoration through multi-target mechanisms. Quantum mechanical (ONIOM) optimizations and molecular dynamics simulations confirmed the stability and favorable interaction profiles of the selected protein-ligand complexes, resembling that of navtemadlin, a known MDM2 inhibitor. This multiscale, accuracy-boosted workflow introduces a novel data-curation strategy that substantially enhances AI model performance and enables efficient drug repurposing against challenging cancer targets.

Keywords:  MDM2; docking; drug repurposing; machine learning; selective cleaning

DOI:  https://doi.org/10.3390/molecules30142992
ESMO Open. 2025 Jul 30. pii: S2059-7029(25)01409-7. [Epub ahead of print]10(8): 105540

Molecular profile and clinical impact of MDM2 amplification in patients with advanced biliary tract cancer.

H Yoon, H Jeong, I Park, H-M Chang, D Kim, C O Sung, J S Lee, B-Y Ryoo, K-P Kim, C Yoo.

   BACKGROUND: MDM2, a negative regulator of p53, has emerged as a potential therapeutic target as its inhibition can restore p53 tumor suppressor activity in MDM2-amplified tumors, including subsets of biliary tract cancer (BTC). However, the genomic and clinical characteristics of MDM2-amplified BTC remain poorly understood.
MATERIALS AND METHODS: Patients with advanced BTC who underwent tissue-based targeted next-generation sequencing and received first-line gemcitabine plus cisplatin (GemCis)-based chemotherapy at Asan Medical Center, Seoul, Korea, between January 2016 and December 2023 were included. Clinicogenomic characteristics and survival outcomes were compared according to the presence of MDM2 amplification with wild-type TP53 (MDM2-amp/TP53-WT). Propensity score (PS) matching was carried out to balance baseline characteristics between patients with and without MDM2-amp/TP53-WT.
RESULTS: Among 813 patients, there were 41 patients (5.0%) with MDM2-amp/TP53-WT, demonstrating no significant association with the primary tumor site: intrahepatic cholangiocarcinoma (4.7%), extrahepatic cholangiocarcinoma (3.7%), and gall-bladder cancer (8.0%) (P = 0.111). Overall, clinical characteristics did not differ according to MDM2-amp/TP53-WT status. Actionable alterations, including ERBB2 amplification (2.4% versus 10.6%) and IDH1 mutation (2.4% versus 6.9%), were less common in MDM2-amp/TP53-WT tumors. In both unmatched and PS-matched populations, MDM2-amp/TP53-WT was associated with significantly longer progression-free survival with first-line GemCis-based therapy [in PS-matched analysis: median 9.6 versus 6.9 months, hazard ratio (HR) 0.63, P = 0.035] and longer, but not statistically significant, overall survival (in PS-matched analysis: median 20.3 versus 16.4 months, HR 0.81, P = 0.267).
CONCLUSIONS: In advanced BTC, tumors harboring MDM2-amp/TP53-WT exhibited distinct mutational patterns with limited other actionable alterations and were associated with better survival outcomes following first-line GemCis-containing chemotherapy. Further investigation of MDM2-targeted therapies for this subset is warranted.

Keywords:  MDM2; TP53; biliary tract cancer; cholangiocarcinoma; cisplatin; gemcitabine

DOI:  https://doi.org/10.1016/j.esmoop.2025.105540
Biochem Pharmacol. 2025 Jul 26. pii: S0006-2952(25)00456-3. [Epub ahead of print]241 117191

Dihydroartemisinin inhibits NSCLC by targeting MDM2/c-Myc axis independent of p53.

Huijuan Ling, Jing Tang, Yayu Zhu, Ke Niu, Ping Qiu, Renjie Chen, Liwen Chen.

  The antimalarial agent Dihydroartemisinin (DHA) has significant potential for drug repurposing for cancer therapy including non-small cell lung cancer (NSCLC). However, its underlying anti-tumor mechanisms remain to be elucidated. In this study, we demonstrated that DHA suppressed the mouse double minute 2 (MDM2) in A549 and H1299 cells, whereas MDM2 overexpression effectively restored DHA's inhibition on both NSCLC cell lines. We showed that DHA acted via phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase (JAK)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathways to inhibit MDM2 expression. Being an established MDM2 target, p53 was significantly upregulated in p53 wild-type A549 cells upon DHA treatment both in vitro and in vivo; however, the mediating role of MDM2 in DHA's suppression on NSCLC is independent of p53 since DHA-treated si-p53 A549 cells had comparable colony formation capacity compared with that of si-Control. The anti-tumor effects of DHA bypass p53 was further implicated using H1299, a cell line which is MDM2-overexpressed but p53-null. Instead, c-Myc was observed to mediate the effects of DHA/MDM2 axis as co-immunoprecipitation (Co-IP) analysis showed the direct protein interaction between MDM2 and c-Myc, both were substantially reduced upon DHA treatment. Furthermore, c-Myc overexpression effectively restored DHA's suppression on proliferation, and DHA's induction on apoptosis of A549 and H1299 cells. Finally, immunohistochemistry (IHC) analysis showed that in vivo administration of DHA substantially reduced both MDM2 and c-Myc expression in xenograft murine models. Taken together, our results demonstrated that DHA inhibits NSCLC by targeting MDM2/c-Myc axis independent of p53.

Keywords:  Dihydroartemisinin; MDM2; NSCLC; P53; c-Myc

DOI:  https://doi.org/10.1016/j.bcp.2025.117191
Biosystems. 2025 Jul 29. pii: S0303-2647(25)00150-9. [Epub ahead of print] 105540

Uncovering dual oscillatory regimes in p53-mdm2 dynamics: A data-driven modeling approach with implications for cancer progression.

Kathryn K Menta, Majid Bani-Yaghoub, Bi-Botti C Youan.

  Quantifying the dynamic interplay between p53 and Mdm2 is critical for uncovering their roles in cancer progression and therapeutic targeting. Experimental studies have shown that p53-Mdm2 interactions exhibit oscillatory behavior in response to DNA damage. However, several mathematical models fail to sustain these oscillations or do not fit well with the experimental data, instead converging to constant steady-state values of p53 and Mdm2, which is unrealistic. In this study, we develop a simple yet robust ordinary differential equation model that accurately quantifies different stable periodic solutions (limit cycles) for p53-Mdm2 dynamics. Specifically, using a two-step numerical calibration algorithm, we validate the model against four experimental datasets. The calibrated model demonstrates strong data fit and reveals two distinct oscillatory regimes: one where Mdm2 oscillates with an amplitude 2.67 times greater than that of p53, and another where Mdm2 shows variable but consistently smaller oscillations than p53. The observed variability in oscillatory behavior may contribute to tumor progression by shortening overall p53 activity windows, thereby limiting the time available to initiate apoptosis and DNA repair.

Keywords:  Data-driven modeling; Limit cycle; Mdm2; Periodic behavior; p53

DOI:  https://doi.org/10.1016/j.biosystems.2025.105540
Ann Clin Lab Sci. 2025 May;55(3): 347-353

HDM-2-Targeting Peptide PNC-27 Kills Cervical Cancer Cells but not Normal Cervical Cells.

Patryck K Krzesaj, Shabnam Seydafkan, Anna I Miller, Hui Ting Chen, Prem Premsrirut, Alfred Shim, Steven Mcglinchey, Ehsan Yazdi, Paul Brandt-Rauf, Miriam Silberstein, Gholamali Jahari, Richard D Feinman, Matthew R Pincus.

OBJECTIVE: The peptide PNC-27 has been found to kill many different endodermal solid tissue and hematopoietic cancer cells but has no effect on normal cells. The mechanism involves binding to the HDM-2 protein, which is expressed in the membranes of cancer cells but not in normal (untransformed) cells. Our objectives in the current study are to determine 1) if PNC-27 is lethal to squamous cervical epithelial cancer cells but not to untransformed squamous cervical cells; 2) if membrane-bound HDM-2 is expressed uniquely in cervical cancer cells; and 3) whether HDM-2 is stable for detection in different types of preservative solutions.
METHODS: We determined dose response curves for incubation of PNC-27 with the human squamous cervical cancer cell line HTB-35 (also called SiHa cells) and with the untransformed human squamous cervical cell line, PCS-480. Cell viability was determined using the MTT and LDH release assays. Finally, slot blots and flow cytometry were used to determine membrane expression of HDM-2 using a polyclonal anti-HDM-2 antibody.
RESULTS: We found that PNC-27 is cytotoxic even at low doses (IC50=12.4 μM) to the human HTB-35 cervical cancer squamous epithelial cell line but not to a counterpart normal human PCS-480 cell line. We found that HTB-35 cells express high levels of HDM-2 proteins in their membranes both in cell culture and in alcoholic preservative solutions but that the normal PCS-480 cells do not. Consistent with previous results, the data suggest that cervical cancer cells express HDM-2 in their membranes and that this is the target for PNC-27.
CONCLUSIONS: PNC-27 kills cervical squamous cancer but not normal cervical cells due to the unique expression of HDM-2 in the cervical squamous cell membranes. Thus, PNC-27 may be an effective drug against this cancer. Our results further suggest that the expression of membrane-bound HDM-2 on cervical cancer cells is stable both in cell culture media and in alcoholic preservative fluid.