bims-midomi 2025-08-24 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–08–24
eight papers selected by
Gavin McStay, Liverpool John Moores University

Bionic Power Play: Dual-Targeting MDMX/MDM2 to Reboot p53 to Beat Lung Adenocarcinoma's Immune Tricks.
A Dual-Specificity d-Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy.
Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis.
In-frame germline TP53 variant impairs p53 oligomerization and predisposes to cancer.
Synergistic effect of MDM2 inhibitors and radiotherapy in endometrial cancer.
Ubiquitin Ligase MDM2 Regulates Chondrocyte Damage, Ferroptosis, and Oxidative Stress by Modulating the Ubiquitination Level of CDKN1A.
Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.
Echinacoside suppresses macrophage lipid accumulation and attenuates atherosclerosis via the MDM2/PPARγ/ABCA1 signaling axis.

Int J Nanomedicine. 2025 ;20 9885-9897

Bionic Power Play: Dual-Targeting MDMX/MDM2 to Reboot p53 to Beat Lung Adenocarcinoma's Immune Tricks.

Solomon Wong, Lu Xu, Weiming You, Wangxiao He, Xiaoqiang Zheng, Zhongquan Qi.

   Background and Aim: MDM2 and MDMX are key regulators of the tumor suppressor p53 and are implicated in immune escape mechanisms in lung adenocarcinoma. Overexpression of these proteins inhibits p53 activity, limiting the immune system's ability to recognize and clear tumor cells, contributing to resistance against immune checkpoint inhibitors (ICIs). This study introduces a novel bionic peptide nanodrug, E@MDP, designed to target both MDM2 and MDMX, reactivate p53, and enhance the effectiveness of PD-1 immune checkpoint therapy in lung cancer.
Methods: E@MDP is constructed using a gold-mediated self-assembly method to form peptide-loaded nanoparticles, which are then encapsulated in erythrocyte membranes, enhancing stability and cell penetration. The physicochemical properties of the bionic nanodrug were evaluated, and its therapeutic efficacy was validated in vitro in LLC cells and in vivo using a syngeneic subcutaneous lung adenocarcinoma mice model.
Results: In vitro, E@MDP reinstated functional p53 activity, demonstrating a 2.46-fold upregulation compared to control groups, and significantly promoted tumor cell apoptosis, exhibiting a 3.9-fold enhancement. In vivo, E@MDP potentiated PD-1 checkpoint blockade by reprogramming the tumor immune microenvironment, ultimately driving a nearly two-fold enhancement in tumor regression versus monotherapies. Importantly, the E@MDP nanodrug exhibited favorable safety profiles, with no significant toxicity observed in preclinical models.
Conclusion: The E@MDP is a promising strategy for lung cancer immunotherapy and overcomes several limitations of conventional peptide drugs. The bionic nanodrug platform holds great potential for broader applications in cancers characterized by immune evasion.

Keywords:  MDM2/MDMX; immunotherapy; lung adenocarcinoma; nanomedicine; peptide

DOI:  https://doi.org/10.2147/IJN.S533208
J Med Chem. 2025 Aug 18.

A Dual-Specificity d-Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy.

Chongbing Liao, Jin Yan, William D Tolbert, Xishan Chen, Marzena Pazgier, Weiyue Lu, Changyou Zhan, Wuyuan Lu.

Designing metabolically stable peptides to target interactions of the tumor suppressor protein p53 with the two oncogenic proteins MDM2 and MDMX represents an attractive approach to harvesting "high-hanging fruits" often inaccessible to traditional anticancer drug discovery and development efforts. Here, we report the design of a proteolysis-resistant d-dodecapeptide, termed DPMI-ω (EFWYVEp-ClFEKLLR), capable of disrupting the p53-MDM2/MDMX complex by antagonizing MDM2 and MDMX. DPMI-ω, upon fabrication on gold nanoparticles, efficiently traversed tumor cells and killed them by reactivating the p53 signaling pathway. Further, DPMI-ω inhibited B16 melanoma growth in vivo and, when combined with an anti-PD1 antibody, powerfully augmented the efficacy of immunotherapy by expanding CD3+/CD8+ cytotoxic T cells and suppressing CD4+/CD25+ regulatory T cells. Our work validates the design of a therapeutically viable anticancer peptide, showcasing its potential in combination therapy to treat patients with tumors that are otherwise resistant or poorly responsive to antitumor immunotherapy.

DOI: https://doi.org/10.1021/acs.jmedchem.4c02057
bioRxiv. 2025 Aug 13. pii: 2025.08.12.669925. [Epub ahead of print]

Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis.

Renyta Moses, Alexandra Indeglia, Alison S Levine, Ryan Hausler, Gregory Kelly, Sven A Miller, Isabel Anez, Melissa Heller, Rosella Delgado, Caitlin Orr, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Sophie R Cahill, Luke D Maese, John Karanicolas, Judy E Garber, Maureen E Murphy, Kara N Maxwell.

The p53 tumor suppressor binds DNA cooperatively as a tetramer, mediated by salt-bridge interactions between p53 residues E180 and R181. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared to patients with hotspot dominant negative loss of function TP53 variants. Despite this phenotype, we find that p53 R181H and R181C variants have significantly reduced ability to bind to p53 promoter/enhancer target sequences and transactivate p53 target genes, similar to null variants. However, p53 R181H and R181C retain wild-type p53 structure and tetramerization. In addition, R181-mutant cells undergo apoptosis through wild-type p53 activity at the mitochondria. These results indicate that retention of transcription-independent p53 tumor suppressor function results in a reduced penetrance cancer risk syndrome in humans.
Statement of Significance: Inherited TP53 variants cause Li-Fraumeni Syndrome (LFS), which has significant phenotypic heterogeneity in lifetime cancer risk. Our study shows that retention of transcription-independent p53 functions, despite loss of p53 transactivation activity, results in a reduced penetrance phenotype. Classification of TP53 variants should incorporate assays of transcriptional and non-transcriptional functions.

DOI: https://doi.org/10.1101/2025.08.12.669925
Sci Rep. 2025 Aug 19. 15(1): 30459

In-frame germline TP53 variant impairs p53 oligomerization and predisposes to cancer.

Lucie Vanikova, Eva Machackova, Barbora Nemcova, Jana Soukupova, Silvia Petrezselyova, Klara Novakova, Marcela Zenatova, Sarka Pavlova, Petra Kleiblova, Zdenek Kleibl, Lenka Foretova, Libor Macurek.

  Germline loss-of-function variants in TP53 cause Li-Fraumeni syndrome (LFS) characterized by an early onset of various cancer types including sarcomas, adrenocortical carcinoma, and breast cancer. The most common are mutations in the DNA binding domain of p53, but alterations in the oligomerization domain also cause LFS with variable level of penetrance. Here we report identification of a novel germline in-frame deletion TP53 variant c.1015_1023del p.(E339_F341del) in a family with early-onset breast cancer and other malignancies. Using functional testing, we found that a short deletion in the oligomerization domain in the p.E339_F341del variant severely impaired transcriptional activity of p53 in human cells and in a yeast model. The loss of the transactivation activity was consistent with an observed defect in formation of p53 tetramers. Finally, we found that cells expressing the p.E339_F341del variant were insensitive to inhibition of MDM2 by nutlin-3 confirming the functional defect. We conclude that the in-frame germline c.1015_1023del TP53 variant encodes a transcriptionally inactive protein and promotes LFS with a high penetrant cancer phenotype.

Keywords:  Cancer; Li Fraumeni syndrome; TP53; p53

DOI:  https://doi.org/10.1038/s41598-025-14684-8
NPJ Precis Oncol. 2025 Aug 18. 9(1): 290

Synergistic effect of MDM2 inhibitors and radiotherapy in endometrial cancer.

Roberto Vargas, Aaron Petty, Daniel J Lindner, Yvonne Parker, Brian Yard, Arda Durmaz, Kristi Lin-Rahardja, Ofer Reizes, Robert Debernardo, Jacob Scott.

Endometrial cancer (EC) is the most common type of gynecologic malignancy in the United States, with over 69,120 new cases expected in 2025. The total number of mortalities surpasses that of ovarian cancer. Despite our ability to identify different biological clusters of EC, we have yet to understand the functional impact of key genomic alterations associated with varying prognoses and exploit this knowledge for therapeutic benefits. Our overarching goal is to understand how genomic alterations impact radiotherapy response in EC, and whether manipulation of these signaling pathways could be utilized as a radio-sensitization strategy. Given that TP53-mutated ECs portend the worst prognoses and seem to benefit from escalation of therapy above that of radiotherapy alone, we first focused our attention on understanding the impact of this genomic aberration on radiation response. Using high-throughput in vitro profiling, genomic manipulation, and in vivo studies, we demonstrated that p53 signaling plays a significant role in the radiotherapy response in EC, thus providing a biological rationale for observed clinical trial findings. We also leveraged this same finding to test a therapeutic approach driving p53/p21 signaling using murine double minute-2 (MDM2) inhibitors, subsequently demonstrating synergism with radiation. Thus, MDM2 inhibitors could be considered as a novel radiosensitizing approach for EC.

DOI: https://doi.org/10.1038/s41698-025-01063-9
Int J Rheum Dis. 2025 Aug;28(8): e70384

Ubiquitin Ligase MDM2 Regulates Chondrocyte Damage, Ferroptosis, and Oxidative Stress by Modulating the Ubiquitination Level of CDKN1A.

Kaihong Gui, Xiaosong Li, Junlai Song, Ao Li, Jun Fan, Lin Huang.

   BACKGROUND: Osteoarthritis (OA) is a common degenerative disease involving pathological changes in joint tissues, which seriously affects the quality of life of patients. It was reported that both Cyclin dependent kinase inhibitor 1A (CDKN1A) and ubiquitinating enzyme MDM2 exhibited abnormal expression in OA. However, it is currently unclear whether there is a specific regulatory mechanism between the two.
METHODS: Firstly, C28/I2 cells were treated with IL-1β to construct an in vitro cell model of OA, while qRT-PCR and western blot were used to detect the mRNA and protein levels of CDKN1A and MDM2. C28/I2 cell viability, apoptosis, and the release of inflammatory factors were measured by CCK-8, flow cytometry, and ELISA kits. In addition, the levels of Fe2+, glutathione (GSH), reactive oxygen species (ROS), and Malondialdehyde (MDA) were evaluated by corresponding kits. Subsequently, the relationship between MDM2 and CDKN1A was predicted by the UbiBrowser website, and the ubiquitination level of CDKN1A and the interaction between them were verified by western blot and Co-IP technology. Cycloheximide (CHX) exposure was used to assess mRNA stability.
RESULTS: CDKN1A was downregulated in OA cartilage tissues and IL-1β induced C28/I2 cells, while overexpression of CDKN1A enhanced C28/I2 cell activity and inhibited cell apoptosis. Meanwhile, the release of IL-6 and TNF-α as well as ferroptosis and oxidative stress, were also hindered by CDKN1A overexpression. MDM2 was highly expressed in OA patients and in IL-1β induced C28/I2 cells and mediated the ubiquitination modification of CDKN1A. Most importantly, MDM2 knockdown alleviated IL-1β-induced chondrocyte damage via upregulating CDKN1A.
CONCLUSION: MDM2 downregulated the level of CDKN1A in chondrocytes by mediating the ubiquitination modification of CDKN1A, leading to impaired chondrocyte viability and inducing ferroptosis and oxidative stress.

Keywords:  CDKN1A; MDM2; OA; ferroptosis; ubiquitination

DOI:  https://doi.org/10.1111/1756-185x.70384
FEBS J. 2025 Aug 17.

Mutant p53 affects the mitochondrial proteome, promoting mitochondrial fragmentation and OXPHOS in pancreatic ductal adenocarcinoma cells.

Maria Poles, Raffaella Pacchiana, Chiara Mortali, Barbara Cisterna, Nidula Mullappilly, Adriana Celesia, Federica Danzi, Martina Gaspari, Daniela Cecconi, Massimo Donadelli, Alessandra Fiore.

  Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by poor prognosis and frequent gain-of-function mutations in the TP53 tumor suppressor gene. Given the crucial role of mutant p53 in the context of metabolic reprogramming and aggressive tumor behavior, we explored its role on mitochondria, which may present a valuable therapeutic target. In this study, we characterized the unique mitochondrial proteome observed in PDAC cells harboring the gain-of-function TP53R273H mutation and discovered a strong mutant p53-dependent upregulation of myosin heavy chain 14 (MYH14), a nonmuscle myosin, implicated in mitochondrial dynamics. We deeply investigated the role of mutant p53 in the regulation of mitochondrial architecture and functionality in PDAC cells. Our morphological and morphometric analyses with transmission electron microscopy and three-dimensional confocal imaging revealed that mutant p53 induced marked mitochondrial fragmentation, whereas wild-type p53 stimulated mitochondrial elongation. Interestingly, the fragmented mitochondrial morphology is associated with higher mitochondrial respiration levels and more efficient mitochondrial cristae. These findings support the role of oncogenic mutant p53 isoforms in inducing mitochondrial fragmentation through a mechanism involving MYH14, resulting in an increased oxidative phosphorylation level that may support PDAC cell growth and aggressiveness.

Keywords:  MYH14; mitochondrial dynamics; mutant p53; pancreatic ductal adenocarcinoma cancer metabolism

DOI:  https://doi.org/10.1111/febs.70223
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Aug 15. pii: S1388-1981(25)00089-7. [Epub ahead of print]1870(7): 159681

Echinacoside suppresses macrophage lipid accumulation and attenuates atherosclerosis via the MDM2/PPARγ/ABCA1 signaling axis.

Qin-Yi Zhou, Jing Zhou, Zhao-Bing Li, Qun Wang, Duo Gong, Wang Liu, Chao-Ke Tang.

  Macrophage cholesterol efflux, a critical step in reverse cholesterol transport, plays a pivotal role in the attenuation of atherosclerosis. Echinacoside, a natural compound with anti-inflammatory, antioxidant, and antitumor properties, has emerged as a potential therapeutic agent for atherosclerosis. However, the mechanisms underlying its anti-atherosclerotic effects remain unclear. In this study, we aimed to investigate the effects of echinacoside on lipid accumulation in macrophage-derived foam cells and on atherosclerotic progression in apoE-/- mice. Our key findings indicated that echinacoside upregulated ABCA1 expression, enhanced macrophage cholesterol efflux, and reduced lipid accumulation by modulating MDM2/PPARγ signaling. Additionally, echinacoside alleviated atherosclerotic progression in high-fat diet-fed apoE-/- mice. MDM2 overexpression with pcDNA3.1-MDM2 eliminated the effects of echinacoside on ABCA1 and PPARγ upregulation, macrophage cholesterol efflux, and lipid accumulation. In conclusion, echinacoside inhibits macrophage lipid accumulation and alleviates atherosclerotic progression via the MDM2/PPARγ/ABCA1 signaling pathway.

Keywords:  ATP-binding cassette transporter A1; Atherosclerosis; Cholesterol efflux; Echinacoside; Murine double minute 2; Peroxisome proliferator-activated receptor-gamma

DOI:  https://doi.org/10.1016/j.bbalip.2025.159681