bims-midomi 2025-05-04 papers

Nat Commun. 2025 Apr 26. 16(1): 3934

p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer.

Irene Herranz-Montoya, Mariana Angulo-Aguado, Cristian Perna, Sladjana Zagorac, Luis García-Jimeno, Solip Park, Nabil Djouder.

Incidence of colorectal cancer (CRC) is increasing likely due to different mechanisms driving initiation and progression. The initial model proposed by Fearon and Vogelstein posits it as a multi-hit neoplasia, originating from adenomatous-polyps induced by WNT activation, ultimately progressing to aggressiveness through p53 loss. Integrating human data with mouse genetics, we redefine this paradigm, highlighting pivotal roles of MYC, oncogenic URI and p53 degradation to initiate CRC. Early APC loss activates MYC to transcriptionally upregulate URI, which modulates MDM2 activity, triggering p53 proteasomal degradation, essential for tumour initiation and mutation burden accrual in CRC mice. Remarkably, reinstating p53 levels via genetic URI depletion or p53 super-expression in CRC mice with WNT pathway activation prevents tumour initiation and extends lifespan. Our data reveal a "two-hit" genetic model central to APC loss-driven CRC initiation, wherein MYC/URI axis intricately controls p53 degradation, offering mechanistic insights into transitional mutation acquisition essential for CRC progression.

DOI: https://doi.org/10.1038/s41467-025-59282-4

Sci Rep. 2025 Apr 27. 15(1): 14731

Mechanistic insights into proteasome inhibitor MG132 induced apoptosis in melanoma A375 cells.

Meng Xu, Ziqing Zhang, Xinyi He, Peixi Zhang, Hengyuan Zhang, Yuanxi Xia, Jiaming Zhou, Jia Liu, Xiaotong Ye, Jieqing Liu.

Despite advancements in melanoma therapy, the prognosis remains unfavorable for many patients. The proteasome inhibitor MG132 has shown therapeutic potential through pathway regulation, yet its precise mechanisms in melanoma require systematic elucidation. Using A375 melanoma cells, we conducted multi-modal investigations combining cytotoxicity assessment (CCK8), migration analysis (wound healing), apoptosis quantification (flow cytometry), and proteomic profiling (western blot) to dissect MG132's molecular mechanisms. Our findings revealed MG132's potent anti-tumor activity with an IC50 of 1.258 ± 0.06 µM, significantly suppressing cellular migration at therapeutic concentrations. Apoptosis assays demonstrated concentration-dependent effects, with 2 µM treatment inducing early apoptosis in 46.5% and total apoptotic response in 85.5% of cells within 24 h. Mechanistic studies uncovered MG132's dual regulatory capacity: (1) Through MDM2 inhibition, it activated p53/p21/caspase-3 axis while suppressing CDK2/Bcl2, triggering cell cycle arrest and DNA damage cascades; (2) MAPK pathway activation emerged as a critical apoptosis driver. Notably, western blot analysis established dose-responsive modulation of these molecular targets, confirming pathway specificity. Our results position MG132 as a multi-target agent capable of simultaneously disrupting proliferative signaling and activating apoptotic machinery. The observed MAPK-mediated apoptosis mechanism provides novel insights for melanoma therapeutics, suggesting that combinatorial targeting of proteasomal and MAPK pathways may enhance treatment efficacy.

Keywords: Antitumor; Apoptosis effects; MG132; Melanoma

DOI: https://doi.org/10.1038/s41598-025-99151-0

Oncogenesis. 2025 May 02. 14(1): 14

FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2/MDMX and inactivation of p53.

Djazia Haferssas, Marion Dubuissez, Jonatan Barrera-Chimal, Clémence Messmer, El Bachir Affar, Bruno Larrivée, Xue-Song Liu, Casimiro Gerarduzzi.

Aberrant Receptor Tyrosine Kinase (RTK) signaling allows cancer cells to modulate survival, proliferation, and death, leading to tumorigenesis and chemoresistance. In leukemia, the RTK FMS-Related Tyrosine Kinase 4 (FLT4) (also known as VEGFR3, Vascular Endothelial Growth Factor Receptor- 3) is deregulated and correlates with cancer progression. However, the underlying consequences of its deregulation remain to be determined. Moreover, chemotherapy treatment requires that cancer cells retain a wild-type p53 to respond to DNA damage by tumor-suppressing activities, i.e. apoptosis. p53 activity is predominantly limited by its two major negative regulators, MDM2 and MDMX, which inactivate p53 by promoting its degradation and/or cytoplasmic localization. In this study, we have shown that activation of FLT4 by either overexpression or binding of its ligand, VEGFC, increases MDM2/MDMX stability, inactivates p53, and leads to resistance to DNA-damaging therapies. Moreover, we found that MDMX Ser-314 phosphorylation, a consensus sequence of CDK4/6, increases MDMX stability, which subsequently affects MDM2 and p53 degradation and could be reversed by the CDK4/6 inhibitor Palbociclib. More importantly, leukemic cells treated with Palbociclib were more susceptible to DNA-damaging induction of apoptosis and had reduced cell proliferation. Leukemic cells overexpressing FLT4 displayed accelerated proliferation when injected into NOD-SCID mice as compared to wild-type cells. Altogether, our research proposes an innovative way to reactivate p53 in leukemia through the pharmacological inhibition of FLT4 signaling, which could serve as a potential treatment option. Schematic representation of FLT4-mediated MDM2/MDMX complex stabilization and suppression of p53 activity. VEGFC triggers FLT4 activation, leading to CDK4/6 activation, which phosphorylates MDMX on Ser-314. As a result, MDMX levels increase and bind to MDM2, stabilizing the MDM2/MDMX complex. This complex binds to p53, facilitating its suppression by reducing its transcriptional activity or enhancing its export to the cytoplasm for proteasomal degradation. Consequently, p53 inactivation promotes their survival, proliferation, and resistance to chemotherapy-induced apoptosis. The figure was created in BioRender.com.

DOI: https://doi.org/10.1038/s41389-025-00552-7

Cancer Genomics Proteomics. 2025 May-Jun;22(3):22(3): 444-457

MDM2 Knockdown Reduces the Oncogenic Activities and Enhances NIS Protein Abundance in Papillary Thyroid Cancer.

Daniel Hueng-Yuan Shen, Hung-Ping Chan, Fu-Ren Tsai, Yu-Li Chiu, Tsung-Jung Liang, Yunying She, An-Chi Liu, Hui-Ying Yeh, Kuo-Wang Tsai, Sung-Chou Li.

BACKGROUND/AIM: Despite the excellent prognosis post thyroidectomy and radioiodine therapy, papillary thyroid cancer (PTC) patients still undergo dismal outcomes, especially when tumors undergo de-differentiation and thus progress to radioiodine refractory status. Our knowledge on the pathogenesis mechanisms of PTC and NIS protein (responsible for iodine uptake) activity is still behind satisfaction. To increase our knowledge on these issues, we conducted this study.
MATERIALS AND METHODS: We analyzed microarray data to identify the genes differentially expressed between normal and tumor thyroid tissues. Next, pathway enrichment analysis was conducted to derive candidate genes and pathways involved in PTC oncogenesis and NIS activity. The expression of candidate genes was confirmed by an independent TCGA dataset. Then, we used siRNA to knockdown the MDM2 gene to examine the potential pathogenesis mechanisms of MDM2 and MDM2-P53-NIS axis in cells. Also, we examined whether oncogenic activities, including cell proliferation, colony formation, cell migration and cell invasion, were altered with MDM2 knockdown. Moreover, NIS protein intensity in cell membrane was also investigated.
RESULTS: Through analyzing microarray data, pathway enrichment and correlation analyses, we focused on MDM2 since it could be involved in the MDM2-P53-NIS axis. Knockdown of MDM2 significantly reduced the mRNA levels and protein abundance of MDM2. In addition, P53 protein was also elevated with MDM2 knockdown. With MDM2 knockdown, cell proliferation and colony formation were repressed. And, both cell migration and invasion abilities were interfered. Moreover, MDM2 knockdown also enhanced the intensity of membrane NIS protein.
CONCLUSION: MDM2 knockdown not only reduced the oncogenic activities of thyroid cancer but also enhanced the intensity of NIS protein responsible for iodine intake in thyroid gland. Therefore, MDM2 could serve as a prognosis indicator in thyroid cancer.

Keywords: MDM2; NIS protein; Thyroid cancer; oncogenesis

DOI: https://doi.org/10.21873/cgp.20512

J Nat Med. 2025 Apr 28.

Natural products that target p53 for cancer therapy.

Sachiko Tsukamoto.

Wild-type p53 acts as a tumor suppressor, but p53 is frequently mutated and inactivated in tumor cells, promoting cancer progression, invasion, and metastasis. Thus, compounds that reactivate p53 may be leveraged for cancer treatment, and the development of drugs targeting p53 reactivation is actively progressing. Notably, natural products exhibit diverse structures and biological activities and are used as therapeutic agents for various diseases worldwide. This review discusses the natural products that inhibit p53 degradation through p53-Mdm2 interaction, promote p53 reactivation by inducing conformational changes, and exhibit p53-dependent growth inhibition.

Keywords: Cancer therapy; Natural products; Tumor suppressor; p53 reactivation

DOI: https://doi.org/10.1007/s11418-025-01906-6