bims-midomi 2026-01-11 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2026–01–11
nine papers selected by
Gavin McStay, Liverpool John Moores University

MDM2 in Tumor Biology and Cancer Therapy: A Review of Current Clinical Trials.
MDM2 amplification enables selective PROTAC targeting of tumor cells.
PUMA-p53 Dysregulation and Ki-67 Overexpression Define Unfavorable Prognostic Signatures in Colorectal Cancer.
Splicing factor FUS facilitates the progression of PIT1-lineage PitNETs by upregulating MDM2.
A Combined Bioinformatics and Clinical Validation Study Identifies MDM2, FKBP5 and CTNNA1 as Diagnostic Gene Signatures for COPD in Peripheral Blood Mononuclear Cells.
Retroperitoneal Dedifferentiated Liposarcoma With Penetrating Abscess Formation Secondary to Ileal Invasion: A Case Report.
DNA Damage Sensing and TP53 Function as Modulators of Sensitivity to Calicheamicin-Based Antibody-Drug Conjugates for Acute Leukemia.
[Mechanism of icariin in inhibiting spermatogonium apoptosis induced by high-fat diet based on Akt/MDM2/p53 pathway and mitochondrial fusion].
From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor.

Int J Mol Sci. 2025 Dec 22. pii: 99. [Epub ahead of print]27(1):

MDM2 in Tumor Biology and Cancer Therapy: A Review of Current Clinical Trials.

Francesco Russano, Mattia Sturlese, Luigi Dall'Olmo, Francesco Callegarin, Davide Brugnolo, Paolo Del Fiore, Vittoria Patti, Arianna Purpura, Stefano Moro, Marco Rastrelli, Simone Mocellin.

  The Murine Double Minute 2 (MDM2) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53's tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53 but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53's functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment.

Keywords:  MDM2; MDM2 inhibitors; cancer therapy; clinical trial; drug development; p53

DOI:  https://doi.org/10.3390/ijms27010099
Mol Cancer Ther. 2026 Jan 10.

MDM2 amplification enables selective PROTAC targeting of tumor cells.

Jiandong Chen, Zainab Fatima, Lihong Chen, Mulan Yin, Yunpeng Cui, Jianfeng Cai.

PROTACs are bivalent molecules that simultaneously bind to proteins of interest and cellular ubiquitin E3 ligases to promote target degradation. Tumor-specific expression of E3 should increase therapeutic efficacy and reduce toxicity in cancer therapy applications. The E3 ligases currently employed during PROTAC design such as CRBN, VHL, c-IAP and MDM2 are ubiquitously expressed and not considered tumor-specific. However, MDM2 is part of the p53 negative feedback loop and is dynamically regulated at transcriptional and post-translational levels. MDM2 gene amplification occurs at 4-20% frequency in multiple tumor types. To investigate whether MDM2 can serve as tumor-specific PROTAC E3 in certain setting, we analyzed the benchmark compound A1874 (JQ1-Idasanutlin chimera targeting BRD4) under various conditions that affect MDM2 expression and activity. The results showed that A1874 activity is dependent on p53-mediated induction of MDM2 expression and is inactive in cells with mutant p53. Importantly, A1874 showed on average ~12-fold higher potency in tumor cells with MDM2 amplification compared to non-amplified cells, correlating with enhanced cytotoxicity. The results suggest that tumors with MDM2 amplification or overexpression can be selectively targeted using PROTAC approach.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0990
Cancers (Basel). 2025 Dec 25. pii: 72. [Epub ahead of print]18(1):

PUMA-p53 Dysregulation and Ki-67 Overexpression Define Unfavorable Prognostic Signatures in Colorectal Cancer.

Alexandros Mekras, Dimitrios Tsavdaris, Dimosthenis Mekras, Alexandra Vasilakou, Daniel Paramythiotis, Antonios Michalopoulos, Mattheos Bobos.

  Background/Objectives: Colorectal cancer (CRC) is the third most commonly occurring cancer. Apoptosis is a fundamental cellular process of programmed cell death, and although many pathways for inducing apoptosis may exist, only the intrinsic and the extrinsic pathways have been demonstrated in detail. This study investigated the expression of BAD, BID, BCL2, MDM2, p53, Ki-67, and PUMA in primary CRC, paired lymph node metastases, and adjacent normal mucosa and explored their associations with clinicopathologic features and patient outcomes. Methods: One hundred thirty patients who underwent surgery for resectable CRC were included in the study. FFPE tumor tissue samples were prospectively collected and used for the construction of the TMA blocks from the primary tumor, paired lymph node metastasis, and paired normal mucosa. Immunohistochemistry for BAD, BID, BCL2, MDM2, p53, Ki-67, and PUMA antibodies was performed. Results: Univariate analysis showed reduced cancer-specific (CSS), disease-free (DFS), and overall survival (OS) in patients with lymphatic invasion, ≥4 positive lymph nodes, poorly differentiated tumors, older age (≥65), right-sided tumors, stage IIIC disease, or no chemotherapy. Multivariate analysis identified lymphovascular invasion, ≥4 metastatic nodes, and high Ki-67 as independent predictors of worse DFS and CSS, with low BAD expression additionally predicting DFS. For OS, adverse predictors included nodal burden, tumor location, absence of chemotherapy, and high p53, MDM2, and Ki-67 expression. Notably, combined high PUMA and low p53 expression independently predicted poorer CSS and OS. Conclusions: High expression of PUMA combined with low expression of p53 and a high expression of Ki-67 were independent unfavorable prognostic indicators for both OS and CSS. Further studies are required to clarify the prognostic and therapeutic role of these markers in CRC.

Keywords:  PUMA; anti-apoptotic; cancer specific survival; colorectal cancer; mdm2; overall survival; p53; prognostic indicators; right colon cancer

DOI:  https://doi.org/10.3390/cancers18010072
Theranostics. 2026 ;16(6): 3032-3049

Splicing factor FUS facilitates the progression of PIT1-lineage PitNETs by upregulating MDM2.

Xu Wang, Jiang Li, Chenggang Jiang, Chengkai Zhang, Linhao Yuan, Tieqiang Zhang, Yuqi Liu, Shunchang Ma, Peng Kang, Deling Li, Xiudong Guan, Jian Chen, Wang Jia.

  Background: Splicing factors play pivotal roles in mRNA processing and are implicated in tumor progression. The aberrant expression of splicing factors is closely associated with the invasiveness and secretion profiles of pituitary neuroendocrine tumors (PitNETs). In this study, we explored the involvement of splicing factors in PIT1-lineage PitNET progression and assessed the feasibility of targeting the splicing process as a therapeutic approach. Methods: Statistical data on PitNET subtypes were obtained from the National Brain Tumor Registry of China (NBTRC), and gene expression analysis was conducted on 40 clinical samples collected for this study. Transcriptome analysis and RNA immunoprecipitation sequencing (RIP-seq) were utilized to examine FUS-mediated alternative splicing and to identify mRNA binding sites in PitNET cells. Minigene splicing assays were employed to confirm the specific exonic and intronic regions. Additionally, Annexin V/PI assays and JC-1 staining were conducted to evaluate apoptosis. Results: The expression of the splicing factor FUS was elevated in PIT1-lineage PitNETs and was correlated with increased proliferative capacity and reduced apoptosis levels. Transcriptome sequencing revealed that the knockdown of FUS led to extensive exon skipping and activated the p53 pathway. In addition to RIP-seq analysis, these findings suggest that FUS contributes to the inclusion of exon 3 to generate full-length MDM2, a well-established negative regulator of p53. Antisense oligonucleotides (ASOs) specifically designed to target binding sequences on pre-mRNAs effectively disrupted the FUS-mediated splicing process, consequently impeding the progression of PitNETs. Conclusions: Our study elucidated the critical function of FUS as a splicing factor in PitNETs. Furthermore, we illustrated that targeting the splicing mechanism associated with MDM2 could restore p53 levels, thereby impeding the progression of PitNETs. This discovery presents a potentially novel strategy for the clinical management of PIT1-lineage PitNETs.

Keywords:  ASO; FUS; MDM2; PitNETs; splicing

DOI:  https://doi.org/10.7150/thno.124068
Int J Mol Sci. 2025 Dec 26. pii: 273. [Epub ahead of print]27(1):

A Combined Bioinformatics and Clinical Validation Study Identifies MDM2, FKBP5 and CTNNA1 as Diagnostic Gene Signatures for COPD in Peripheral Blood Mononuclear Cells.

Innokenty A Savin, Aleksandra V Sen'kova, Andrey V Markov, Olga S Kotova, Ilya S Shpagin, Lyubov A Shpagina, Valentin V Vlassov, Marina A Zenkova.

  Chronic obstructive pulmonary disease (COPD) is often diagnosed after significant lung damage has already occurred, highlighting a need for minimally invasive biomarkers for early detection of COPD development. This study aims to identify transcriptional biomarkers in peripheral blood mononuclear cells (PBMCs). A Weighted Gene Co-Expression Network Analysis (WGCNA) was performed on the GSE146560 transcriptomic dataset. Hub genes were cross-validated using independent transcriptomic data (GSE94916), topology analysis of a COPD-related protein-protein interaction (PPI) network, and a text-mining approach. The top candidate genes were validated using RT-qPCR in a clinical cohort, consisting of 28 COPD patients and 13 healthy volunteers, and their diagnostic value was evaluated using receiver operating characteristic (ROC) analysis. WGCNA identified four gene modules significantly correlated with COPD, the functional annotation of which revealed their enrichment in immune and tissue remodeling pathways. Further analysis of the PPI network topology structure and gene expression revealed a hub gene signature that was significantly upregulated in PBMCs of COPD patients, including MDM2 (6.3-fold, p < 0.001), FKBP5 (7.0-fold, p < 0.001), and CTNNA1 (10.0-fold, p < 0.001). ROC analysis demonstrated high diagnostic accuracy for these genes, with AUC values of 0.849, p < 0.001, for MDM2, 0.957, p < 0.001, for FKBP5, and 0.958, p < 0.001, for CTNNA1. MDM2, FKBP5, and CTNNA1 represent promising, readily accessible PBMC biomarkers for COPD diagnosis.

Keywords:  bioinformatics; biomarkers; chronic obstructive pulmonary disease; differentially expressed genes

DOI:  https://doi.org/10.3390/ijms27010273
Clin Case Rep. 2026 Jan;14(1): e71561

Retroperitoneal Dedifferentiated Liposarcoma With Penetrating Abscess Formation Secondary to Ileal Invasion: A Case Report.

Kenichiro Yambe, Kei Nakagawa, Kuniharu Yamamoto, Hiroto Sakurai, Kazuhiro Takami, Noriko Kondo, Chikashi Shibata, Yu Katayose.

  Liposarcoma is a relatively common malignant soft tissue tumor in adults. Dedifferentiated liposarcoma (DLS) is a particularly invasive subtype characterized by high recurrence rates and a poor prognosis. We describe a case of a retroperitoneal liposarcoma with poor differentiation that presented with peritonitis accompanied by ileal infiltration and perforating abscess formation. A 77-year-old male presented to our hospital with abdominal pain and fever. Computed tomography revealed a 13 cm tumor in the right lower abdomen with internal air density. An ileocecal resection was performed. Histopathological examination revealed a solid proliferation of spindle-shaped atypical cells. Immunohistochemical results were positive for MDM2 and negative for CD34 and c-kit. Fluorescence in situ hybridization confirmed MDM2 amplification, leading to a diagnosis of dedifferentiated liposarcoma. The postoperative course was initially favorable; however, 6 months later, a penetrating abscess recurred and progressed to an enterocutaneous fistula. Intestinal penetration by dedifferentiated liposarcomas is extremely rare. This case highlights the challenges of preoperative diagnosis, the importance of surgical strategies that balance infection control with curative resection, and the need for multidisciplinary management of recurrence.

Keywords:  MDM2 amplification; abscess; dedifferentiated liposarcoma; enterocutaneous fistula; intestinal penetration; retroperitoneal tumor

DOI:  https://doi.org/10.1002/ccr3.71561
Cancers (Basel). 2025 Dec 25. pii: 67. [Epub ahead of print]18(1):

DNA Damage Sensing and TP53 Function as Modulators of Sensitivity to Calicheamicin-Based Antibody-Drug Conjugates for Acute Leukemia.

Camryn M Pettenger-Willey, George S Laszlo, Margery Gang, Frances M Cole, Colin D Godwin, Sarah Erraiss, Pritha Chanana, Allie R Kehret, Junyang Li, Jacob W Barton, Meghann M Yochim, Eduardo Rodríguez-Arbolí, Roland B Walter.

   BACKGROUND/OBJECTIVES: Approved for treatment of acute leukemia, gemtuzumab ozogamicin (GO) and inotuzumab ozogamicin (InO) are antibody-drug conjugates (ADCs) that deliver a toxic calicheamicin (CLM) derivative. The resistance mechanisms to GO/InO remain incompletely understood.
METHODS: We performed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 screen for CLM sensitivity genes, and then performed confirmatory cytotoxicity assays.
RESULTS: Several DNA damage pathway regulation genes were identified, most notably TP53. Across 13 acute leukemia cell lines, the six TP53-mutant cell lines (TP53MUT) were indeed 10- to 1000-fold less sensitive to CLM than the seven TP53WT cell lines. In five TP53WT/KO syngeneic cell line pairs we generated, TP53KO cells were significantly less sensitive to CLM than their TP53WT counterparts. In TP53WT but not TP53MUT cells, the MDM2 inhibitor and p53 activator, idasanutlin, enhanced CLM cytotoxicity, demonstrating that decoupling of cells from MDM2-p53 regulation sensitizes leukemia cells to CLM. The ATM inhibitors AZD1390 and lartesertib also significantly enhanced CLM efficacy but did so independent of the TP53 status. In contrast, neither an ATR inhibitor, Chk1/Chk2 inhibitor, Chk2 inhibitor, or a PARP inhibitor significantly impacted CLM-induced cytotoxicity across the thirteen cell lines. Together, our studies identify ATM, MDM2, and TP53-which are in the same cellular response to DNA damage pathway-as key modulators of CLM-induced cytotoxicity in acute leukemia cells.
CONCLUSIONS: These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO.

Keywords:  CD22; CD33; CRISPR/Cas9; acute leukemia; calicheamicin; drug screen; gemtuzumab ozogamicin; inotuzumab ozogamicin

DOI:  https://doi.org/10.3390/cancers18010067
Zhongguo Zhong Yao Za Zhi. 2025 Oct;50(20): 5800-5810

[Mechanism of icariin in inhibiting spermatogonium apoptosis induced by high-fat diet based on Akt/MDM2/p53 pathway and mitochondrial fusion].

Ya-Nan Qu, Hai-Xia Zhao, Run-Min Mao, Zi-Hui Gao, Hai-Li Duan, Guang-Sen Li, Chang-Cheng Zhang.

  This study aims to investigate the protective effects of icariin against high-fat diet-induced spermatogonium apoptosis and explore its mechanisms through the protein kinase B(Akt)/murine double minute 2(MDM2)/p53 pathway and mitochondrial fission/fusion. For in vivo experiments, SPF-grade male C57BL/6J mice were randomly grouped as follows: normal diet, high-fat diet, and low(3 mg·kg~(-1)), medium(9 mg·kg~(-1)), and high(27 mg·kg~(-1)) doses of icariin. Testicular morphology was observed by hematoxylin-eosin(HE) staining, and spermatogonium were counted. Meanwhile, spermatogonium apoptosis was detected by terminal-deoxynucleotidyl transferase-mediated nick-end labeling. Considering the metabolism of icariin into icaritin in vivo, icaritin was selected for in vitro study. The apoptosis model of GC-1 cells was established with palmitic acid(PA). The cell viability was measured by the CCK-8 assay to determine the optimal icaritin concentration, and then GC-1 cells were allocated into control, PA, and low-, medium-, and high-concentration icaritin groups. The apoptosis rate and reactive oxygen species(ROS) level were analyzed by flow cytometry. The expression levels of proteins associated with apoptosis, Akt/MDM2/p53 pathway, and mitochondrial fission/fusion were measured by Western blot. The cysteinyl aspartate-specific proteinase 3(caspase-3) activity was measured by a specific assay kit, and mitochondrial membrane potential by JC-1 staining. Mitochondrial morphology was visualized by confocal microscopy. Finally, GC-1 cells were allocated into the following groups: control, PA, PA+icaritin, and MK2206(Akt inhibitor)+PA+icaritin. The expression levels of proteins associated with apoptosis and Akt/MDM2/p53 pathway were examined by Western blot. The cell apoptosis rate was detected by flow cytometry. The results showed that icariin ameliorated high-fat diet-induced testicular morphological abnormalities and spermatogonium apoptosis. Compared with the PA group, icaritin restored GC-1 cell viability, reduced the apoptosis rate, suppressed intracellular ROS accumulation, downregulated the expression levels of cleaved caspase-3, p-p53(Ser15), p53, as well as the ratio of B-cell lymphoma 2(Bcl-2)-associated X protein(Bax)/Bcl-2, upregulated the expression levels of p-Akt(Ser473), p-MDM2(Ser166), optic atrophy 1(OPA1), and mitofusin 2(MFN2), inhibited the activity of caspase-3, enhanced mitochondrial membrane potential, and restored mitochondrial morphology. MK2206 counteracted the protective effect of icaritin on PA-induced cell apoptosis. Furthermore, MK2206 upregulated the expression levels of cleaved caspase-3 and p-p53(Ser15), as well as the Bax/Bcl-2 ratio, and downregulated the expression levels of p-Akt(Ser473) and p-MDM2(Ser166). These findings suggest that icariin protects against high-fat diet-induced spermatogonium apoptosis potentially through regulation of Akt/MDM2/p53 signaling and promotion of mitochondrial fusion.

Keywords:  Akt/MDM2/p53 signaling pathway; apoptosis; high-fat diet; icariin; spermatogonium

DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250708.401
J Pharm Anal. 2025 Dec;15(12): 101322

From foe to friend: Rewiring oncogenic pathways through artificial selenoprotein to combat immune-resistant tumor.

Weiming You, Zhengjun Zhou, Zhanfeng Li, Jin Yan, Yang Wang.

  Reprogramming oncogenic signaling pathways to generate anti-tumor effects is a promising strategy for targeted cancer intervention, without significant off-target effects. Although reprogramming multi-oncoprotein interactions in a single signaling pathway axis has been shown to achieve sustained efficacy, there are several challenges that limit its clinical application. Herein, we transformed the mouse double minute 2 homolog (MDM2)-heat shock cognate protein 70 (HSC70) axis, a tumor-promoting pathway, into an activator of anti-tumor immunity using the Path-editor, an artificial selenoprotein. Once it enters the cell, Path-editor decomposes into PMI and PPI peptides: PMI inhibits MDM2-mediated p53 degradation and promotes HSC70 expression, while PPI binds to HSC70, enabling its ability to selectively degrade the programmed cell death ligand 1 (PD-L1). As a proof of concept, we tested its performance in microsatellite-stable (MSS) colorectal cancer, which typically displays limited responsiveness to immunotherapy. The results indicated that Path-editor effectively attenuated PD-L1 expression and reversed immune evasion in both CT26 allografts and humanized patient-derived tumor xenograft (PDX) models, thereby inhibiting tumor progression with high biosafety. Therefore, this paper introduces Path-editor as a paradigm for reprogramming oncogenic multi-protein pathways, utilizing selenium-assisted approach to achieve the rapid design of tumor-specific pathway editors. This strategy is expected to reverse immune escape in MSS colorectal cancer and treat difficult malignancies.

Keywords:  Anti-tumor immunity; Artificial microprotein; Cancer therapy; Pro-oncogenic pathways; Reprogramming

DOI:  https://doi.org/10.1016/j.jpha.2025.101322