bims-midomi 2025-04-13 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–04–13
seven papers selected by
Gavin McStay, Liverpool John Moores University

Inhibition of esophageal squamous cell carcinoma progression by MIR210HG and activation of the P53 signaling pathway to promote apoptosis and autophagy.
Selective USP7 inhibition synergizes with MEK1/2 inhibitor to enhance immune responses and potentiate anti-PD-1 therapy in NRAS mutant melanoma.
Reduced myocardial CARF and the underlying implications in left ventricular noncompaction cardiomyopathy.
Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis.
Everolimus and Sunitinib potentially work as therapeutic drugs for infantile hemangiomas.
p53 inhibition during audiogenic kindling in Krushinsky-Molodkina rats attenuates seizure severity and prevents neurodegeneration in the hippocampus.
MIS18BP1 promotes bladder cancer cell proliferation and growth via inactivating P53 signaling pathway.

Eur J Med Res. 2025 Apr 11. 30(1): 269

Inhibition of esophageal squamous cell carcinoma progression by MIR210HG and activation of the P53 signaling pathway to promote apoptosis and autophagy.

Jianyu Wang, Zhenhu Zhang, Liang Song, Xiangyan Liu, Xiaopeng He.

   BACKGROUND: Esophageal squamous cell carcinoma (ESCC) stands among the frequently occurring malignancies. The lack of efficient early detection methods and therapeutic approaches leads to a high mortality rate for ESCC. The long noncoding RNA MIR210HG is strongly related to various malignant tumors. However, its involvement in ESCC remains unexplored. Thus, this investigation aimed to assess the involvement of MIR210HG in ESCC development.
METHODS: The MIR210HG expression was analyzed in numerous tumor types through pan-cancer analysis of The Cancer Genome Atlas(TCGA) database. This research investigated the MIR210HG role in the survival and prognosis of individuals with ESCC. The biological functions of MIR210HG were examined by enrichment analyses, including GO, GSEA, and KEGG. Moreover, immune cell infiltration, tumor microenvironment (TME) characteristics, and immune checkpoint expression levels associated with MIR210HG were explored. To get more insight into the connection between MIR210HG and ESCC, we assessed related gene and protein expression using Western blotting and qRT-PCR. To evaluate the proliferation, invasion, migration, apoptosis, and autophagy of ESCC cells, various techniques were employed, including EdU proliferation tests, monodansylcadaverine (MDC) staining, wound healing assays, cell colony formation, transwell assays, flow cytometry, and an established xenograft mouse model.
RESULTS: MIR210HG exhibited low expression levels in ESCC. High expression of MIR210HG correlated with a higher survival rate among patients. The elevated expression of MIR210HG hindered the ESCC cell's ability to proliferate, invade, and migrate, both in vivo and in vitro settings. Furthermore, a positive correlation between MIR210HG and the P53 signaling pathway was observed, which could affect autophagy and apoptosis in ESCC cells.
CONCLUSIONS: MIR210HG emerges as a pivotal gene in ESCC, influencing both the immunity and prognosis of patients. Moreover, it may affect autophagy and apoptosis via the P53 signaling pathway. Overall, these outcomes present novel ideas for ESCC treatment.

Keywords:  Apoptosis; Autophagy; Esophageal squamous cell carcinoma; MIR210HG; P53 signaling pathway

DOI:  https://doi.org/10.1186/s40001-025-02512-8
J Invest Dermatol. 2025 Apr 07. pii: S0022-202X(25)00384-7. [Epub ahead of print]

Selective USP7 inhibition synergizes with MEK1/2 inhibitor to enhance immune responses and potentiate anti-PD-1 therapy in NRAS mutant melanoma.

Liya Su, Dinghao Wang, Timothy J Purwin, Sophia Ran, Qi Yang, Qingrun Zhang, Weijia Cai.

  Targeted therapy for NRAS mutant melanoma remains an unmet clinical need. We found that inhibiting Ubiquitin Specific Peptidase 7 (USP7) with the selective USP7 inhibitor (USP7i) FT671 inhibited cell proliferation in NRAS mutant melanoma cell lines. In addition, we identified and validated the knockout of TP53BP1, TP53 or CDKN1A conferred resistance to FT671, suggesting the activation of a functional p53 signaling pathway is essential for the efficacy of USP7i. In Nras mutant melanoma isograft models, FT671 treatment delayed tumor growth. Moreover, the combinatorial treatment with FT671 and MEK1/2 inhibitor (MEKi) was synergistic and induced pyroptosis in vitro. In immunocompetent mice, the combined treatment profoundly suppressed tumor growth, prolonged survival and enhanced intratumoral immune cell infiltration, particularly increasing the ratios of CD8+ T cells and mature dendritic cells, indicative of activated antitumor immunity. Notably, the triple combination of USP7i, MEKi, and anti-PD-1 antibody resulted in durable tumor regression, with effects persisting beyond 80 days after treatment cessation. These findings establish USP7i+MEKi as a promising strategy for targeting NRAS, an 'undruggable' mutation in melanoma, and provide a strong rationale for the clinical development of USP7i plus MEKi as an adjuvant therapy to enhance anti-PD-1 immunotherapy in NRAS mutant melanoma patients.

Keywords:  FT671; MEK; NRAS; PD-1; USP7; cutaneous melanoma; p53; pyroptosis; targeted therapy; trametinib

DOI:  https://doi.org/10.1016/j.jid.2025.03.021
Int J Cardiol. 2025 Apr 04. pii: S0167-5273(25)00264-5. [Epub ahead of print] 133221

Reduced myocardial CARF and the underlying implications in left ventricular noncompaction cardiomyopathy.

Liu Hui, Li Xinrun, Xiao Yana, Chen Liyuan, Yin Shangqi, Liu Wuzheng, Zhang Yao, Yubin Wang, Li Chunyan.

   BACKGROUND: Left ventricular noncompaction cardiomyopathy (LVNC) has been used to describe a ventricular phenotype characterized by thick LV trabeculae and the formation of crypts by depression. Some studies have shown that apoptosis of cardiomyocytes leads to impaired development and densification, resulting in LVNC formation. The applicant's previous results showed that CARF protein was specifically down-regulated in myocardial tissue of LVNC disease, and the pathway specifically enriched in LVNC was the p53 apoptosis pathway, and CARF was enriched in the p53 apoptosis pathway.
METHODS: Comparative proteomic analysis by iTRAQ-2DLC-MS/MS was used to screen differentially expressed proteins in heart samples obtained from heart transplantation patients diagnosed with LVNC, ARVC, and HCM in comparison to normal heart samples. Decresing expressed CARF in heart samples from LVNC was further confirmed by Western blot. Immunofluorescence, western blots were used to study the effects of knock out CARF on the structure and function of HL1 cardiomyocytes. Functional and morphological changes were observed by TUNEL staining in cardiomyocytes whose left ventricle knock out CARF.
RESULTS: In our study, CARF protein is specifically down-regulated in myocardial tissue of LVNC disease. The pathway specifically enriched in LVNC is the p53 apoptosis pathway, and CARF is enriched in the p53 apoptosis pathway. We hypothesized that CARF interacts with p53 to influence apoptotic pathway activity resulting in LVNC. In view of the localization and function of CARF in the heart, we hypothesized that knock out the CARF might be involved in the apoptosis pathway and participated in the molecular mechanism of LVNC.
CONCLUSION: Myocardial CARF phosphorylation participate in the apoptosis pathway which result in cardiomyocytes apoptosis. Our findings suggest that decreased myocardial CARF might be involved in the molecular mechanism of LVNC. CARF participates in the occurrence and development of LVNC by mediating the p53 pathway, so as to develop new therapeutic targets for LVNC.

Keywords:  Apoptosis pathway; CARF; LVNC

DOI:  https://doi.org/10.1016/j.ijcard.2025.133221
Clin Cancer Res. 2025 Apr 08.

Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis.

Naval Daver, Jayastu Senapati, Hagop M Kantarjian, Bofei Wang, Patrick K Reville, Sanam Loghavi, Musa Yilmaz, Courtney D DiNardo, Tapan M Kadia, Mhd Yousuf Yassouf, Abhishek Maiti, Sankalp Arora, Guillermo Montalban Bravo, Guilin Tang, Gautam Borthakur, Koji Sasaki, Naveen Pemmaraju, Joie Alvarez, Graciela M Nogueras Gonzalez, Jing Ning, Ghayas C Issa, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Guillermo Garcia-Manero, Hussein A Abbas.

PURPOSE: Magrolimab is a monoclonal antibody directed against macrophage checkpoint CD47 on myeloid leukemia cells that was pre-clinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation.
PATIENTS AND METHODS: In this phase 1b/2 study the triplet combination of azacitidine, venetoclax and magrolimab was evaluated in adult patients with frontline (ineligible for intensive chemotherapy) and relapsed/refractory AML. Azacitidine was dosed at 75mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase 2 dose [RP2D]) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on day 11, 15 and 22 (cycle 1), followed by 30 mg/kg weekly for cycle 2, then 30 mg/kg every 2 weeks cycle 3 and beyond. The primary endpoint was RP2D for phase 1b and rates of composite complete response (CRc) in phase 2.
RESULTS: The frontline cohort included 54 patients (median age 70.1 years); 35 (64.8%) were TP53 mutated (TP53mut). CRc was attained in 34 patients (63%); 49% in TP53mut and 90% in the TP53 wild-type patients. At a median follow-up of 27.9 months, the median event free survival (EFS) and overall survival (OS) was 6.6 months and 9.8 months respectively; for TP53mut patients the median EFS and OS was 5.9 and 7.6 months, while for TP53 wild type it was 9.6 months and 13 months respectively. CRc in the relapsed/refractory cohort (n=52) was 29% and median OS was 3.9 months. The regimen was well tolerated; infections were the most common ≥ grade 3 adverse event (75.4%) with no immune toxicities or deaths related to therapy. scRNAseq was performed on 27 longitudinal samples from 11 TP53mut patients (8 responders). Gene set enrichment analysis revealed enrichment of IFNγ and TNFα signaling in non-responders at baseline, while erythroid differentiation was associated with resistance. Patients at relapse also showed up-regulated CD47 expression and elevated leukemia regeneration score.
CONCLUSIONS: The triplet regimen was safe but did not lead to promising survival outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0229
Pediatr Res. 2025 Apr 05.

Everolimus and Sunitinib potentially work as therapeutic drugs for infantile hemangiomas.

Rongfang Xie, Zhujue Taohuang, Rosalind Kieran, Zhiyu Li, Luying Wang, Changxian Dong, Jianfeng Ge, Xusheng Wang, Miaomiao Li.

BACKGROUND: Infantile hemangiomas (IH) are common vascular tumors in infants, with no well-defined therapeutic agents currently available. Recent studies have explored molecular mechanisms involved in IH progression, but the lack of immortalized hemangioma-derived endothelial cell (iHemEC) models has limited drug discovery efforts.
METHODS: We established an immortalized hemangioma-derived endothelial cell (iHemEC) expressing hemangioma markers and screened 18 potential drugs. Transcriptome profiling and Gene Set Enrichment Analysis (GSEA) were applied to assess the molecular effects of Everolimus and Sunitinib.
RESULTS: Sunitinib, Elimusertib, HIF-1 inhibitor-4, Rebastinib, and Everolimus inhibited iHemEC with lower IC50 than Propranolol and Rapamycin. GSEA showed that PI3K/AKT/mTOR pathway was only downregulated in Everolimus treated cells. Chromosome instability was found specifically in Sunitinib treated cells, which has been reported to cause DNA damage. DNA damage induced ROS and extracellular ROS production was only observed in Sunitinib treated cells. Additionally, Sunitinib can trigger P53 activation and BCL2 downregulation with a dose of 0.2 µM which is fifty times lower than the dose of Everolimus at 10 µM.
CONCLUSION: We successfully developed an iHemEC model for in vitro drug screening and mechanistic study. Everolimus and Sunitinib emerged as promising therapeutic candidates for IH, providing a valuable basis for future research.
CLINICAL PERSPECTIVES: Infantile hemangiomas (IH) are very common tumors in the neonatal period, with an incidence of approximately 2% to 10% among newborns, there are no well-defined therapeutic agents for IH, nor are there established human immortalized cell lines for in vitro studies. We establish an immortalized hemangioma-derived endothelial cell (iHemEC) which highly express markers of hemangioma. Drug screening was performed on iHemEC, Everolimus and Sunitinib were found efficiently induce cell death to iHemEC with much lower IC50 than front line drug Propranolol. Bulk RNAseq and WB analysis showed that Everolimus specifically inhibit PI3K/AKT/mTOR pathway, however Sunitinib induce chromosome instability and DNA damage. Both drugs can trigger P53 dependent cell death. Our study successfully developed an iHemEC cell line suitable for in vitro drug screening and mechanistic study. Sunitinib, VEGFR inhibitor, potentially can applied for the treatment of IH.
IMPACT: Developed a novel immortalized hemangioma-derived endothelial cell (iHemEC) model that replicates key IH features, overcoming limitations of primary cell models. Identified Sunitinib and Everolimus as promising therapeutic candidates with superior efficacy, supported by transcriptome and protein analyses. Revealed distinct drug mechanisms, with Everolimus targeting PI3K/AKT/mTOR and Sunitinib inducing chromosome instability and DNA damage.

DOI: https://doi.org/10.1038/s41390-025-04028-7
Neuroscience. 2025 Apr 08. pii: S0306-4522(25)00290-8. [Epub ahead of print]

p53 inhibition during audiogenic kindling in Krushinsky-Molodkina rats attenuates seizure severity and prevents neurodegeneration in the hippocampus.

Alexey A Kulikov, Alexandra A Naumova, Yulia O Sokolova, Andrey A Suponin, Konstantin A Krasnov, Svetlana D Nikolaeva, Elena V Chernigovskaya, Elena D Bazhanova, Margarita V Glazova.

  In the present study, we analyzed the effects of the p53 inhibitor pifithrin-α (PFT) on the expression of brainstem audiogenic seizures (AGS) and limbic seizures in Krushinsky-Molodkina (KM) rats genetically prone to AGS. To reproduce limbic/mesial temporal lobe epilepsy (TLE)-like condition in KM rats, we used repetitive AGS stimulations (audiogenic kindling) during 14 days. In parallel with AGS stimulations, KM rats received daily intraperitoneal injections of PFT. Our data demonstrated that PFT treatment significantly decreased the duration and severity of both brainstem AGS and limbic seizures. In addition, PFT partially prevented the kindling-induced neurodegeneration and activation of apoptotic mechanisms in the hippocampus of KM rats. Moreover, PFT treatment led to the persistent upregulation of anti-apoptotic Bcl-2, along with GluA2 and GluN2A, glutamate receptor subunits which are involved into the mechanisms supporting cell survival and preventing neuronal hyperexcitability. Altogether, our data confirm that p53 can be considered as a perspective target for the development of novel strategies to mitigate seizure activity and avert its deleterious consequences.

Keywords:  Audiogenic kindling; Glutamate transmission; Hippocampus; Krushinsky-Molodkina rats; Neurodegeneration; Pifithrin-α

DOI:  https://doi.org/10.1016/j.neuroscience.2025.04.013
Med Oncol. 2025 Apr 09. 42(5): 156

MIS18BP1 promotes bladder cancer cell proliferation and growth via inactivating P53 signaling pathway.

WenJing Cao, XueYing Tan, Xuze Li, YuLin Wang, YuQing Zhai, ZongLiang Zhang, JiangShui Yuan, WeiQing Song.

  MIS18 bonding protein 1 (MIS18BP1) is a subunit of MIS18 complex, accumulated specifically at telophase-G1 centromere and regulated apoptosis, proliferation and migration in cancer cells. The mechanisms about how MIS18BP1 regulate Bladder Cancer (BCa) cell development have not been previously unknown. We analyzed MIS18BP1 differential expression in BCa by The Cancer Genome Atlas (TCGA), Gene-Expression Omnibus (GEO) and Universal Protein database. The expression of MIS18BP1 mRNA was tested using qRT-PCR. The expression of MIS18BP1 protein was examined by western blot and immunohistochemistry (IHC) staining. T24 cells were transfected with an LV -MIS18BP1 -RNAi vector to decrease the MIS18BP1 expression. We used a series of experiments to detect the survival, proliferation and migration of T24. The apoptosis was analyzed by Flow cytometry assays. The expression of P53, BAX and Cleaved Casepase-3 was detected by western blot. P53 apoptosis-related proteins, proliferation and migration of cells were analyzed before and after treatment with P53 inhibitors. The expression of MIS18BP1 was higher in BCa tissues compared with control group. Its expression was in relation to clinical stage, depth of invasion and lymph node metastasis. We found that genes closely related to MIS18BP1 are mainly associated with cell cycle, chromosome separation and DNA repair in biological processes. After transfection, we found the proliferative capacity of T24 was significantly reduced. Transwell migration and scratch experiment demonstrated decreased migration. Meanwhile, downregulation of MIS18BP1 resulted in an increase in cell apoptosis. In addition, P53, BAX and Cleaved Casepase-3 were increased, whereas BCL2 protein was decreased in the MIS18BP1-downregulated T24. After treatment with Pifithrin-α, the phenotype of cell proliferation inhibition was restored. MIS18BP1 overexpression may be regulated to poor prognosis in BCa patients. MIS18BP1 may associated with cell apoptosis and proliferation in BC cells. This process may be mediated by P53 signal pathway.

Keywords:  Bladder cancer; Gene-Expression Omnibus; MIS18BP1; P53; The Cancer Genome Atlas

DOI:  https://doi.org/10.1007/s12032-025-02704-6