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Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma

  • Authors:
    • Chueh-Chuan Yen
    • Paul Chih-Hsueh Chen
    • San-Chi Chen
    • Wen-Chi Wu
    • Chiao-Han Yen
    • Yung-Chan Lin
    • Po-Kuei Wu
    • Chao-Ming Chen
    • Jir-You Wang
    • Ta-Chung Chao
    • Muh-Hwa Yang
    • Jonathan A. Fletcher
  • View Affiliations / Copyright

    Affiliations: Department of Medical Research, Division of Clinical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan, R.O.C., Department of Orthopedics and Traumatology, Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei 112201, Taiwan, R.O.C., Department of Oncology, Division of Medical Oncology, Center for Immuno‑oncology, Taipei Veterans General Hospital, Taipei 112201,  Taiwan, R.O.C., Department of Oncology, Division of Medical Oncology, Center for Immuno‑oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, R.O.C., Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
    Copyright: © Yen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 269
    |
    Published online on: April 7, 2025
       https://doi.org/10.3892/ol.2025.15015
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Abstract

Ferroptosis is a form of necrotic cell death characterized by phospholipid oxidation. The cystine‑glutamate antiporter (xCT), composed of solute carrier family 7 member 11 (SLC7A11) and SLC3A2, imports cystine for glutathione synthesis. Glutathione peroxidase 4 (GPX4) requires glutathione to counteract lipid peroxidation and prevent ferroptosis. Erastin, an xCT inhibitor, and Ras‑selective lethal small molecule 3 (RSL3), a GPX4 inhibitor, suppress GPX4 function and induce ferroptosis. Tumor protein p53 (TP53) has a paradoxical role in ferroptosis regulation. Mouse double minute 2 homolog (MDM2), a negative regulator of TP53, is a key oncogene in well‑differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). Therefore, the present study explored the role of ferroptosis in DDLPS treatment response and resistance. Publicly available expression profiles of WDLPS, DDLPS and adipose tissue were analyzed, and the differential expression of ferroptosis‑related genes regulated by the MDM2‑TP53 pathway was identified in WDLPS and DDLPS. In vitro experiments were performed to assess the effects of erastin and RSL3 on the viability, lipid peroxidation and apoptosis of DDLPS cell lines. The results revealed that erastin and RSL3 induced lipid peroxidation and apoptosis, thereby exerting cytotoxic effects. In addition, nutlin‑3, an MDM2 inhibitor, was demonstrated to increase lipid peroxidation and cytotoxicity when applied prior to erastin treatment. Notably, nutlin‑3 also upregulated SLC3A2 expression in DDLPS cell lines, thereby enhancing cystine uptake. This increase in cystine uptake was suppressed by erastin. In addition, nutlin‑3‑induced SLC3A2 upregulation was abolished by TP53 knockdown. Nutlin‑3 combined with erastin or RSL3 reduced absolute p‑4EBP‑1 levels in NDDLS‑1 cells and p‑p70S6 levels in both cell lines, with no significant impact on the p‑4EBP‑1/4EBP‑1 and p‑p70S6/p70S6 ratios. These results indicate that ferroptosis is a therapeutic vulnerability in the response to MDM2 inhibition in DDLPS. Furthermore, combining MDM2 inhibitors with ferroptosis‑inducing agents may provide a potential therapeutic strategy for DDLPS and the role of mTOR in the pro‑apoptotic effect of these combinations deserve further investigation.
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Copy and paste a formatted citation
Spandidos Publications style
Yen C, Chen PC, Chen S, Wu W, Yen C, Lin Y, Wu P, Chen C, Wang J, Chao T, Chao T, et al: Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma. Oncol Lett 29: 269, 2025.
APA
Yen, C., Chen, P.C., Chen, S., Wu, W., Yen, C., Lin, Y. ... Fletcher, J.A. (2025). Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma. Oncology Letters, 29, 269. https://doi.org/10.3892/ol.2025.15015
MLA
Yen, C., Chen, P. C., Chen, S., Wu, W., Yen, C., Lin, Y., Wu, P., Chen, C., Wang, J., Chao, T., Yang, M., Fletcher, J. A."Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma". Oncology Letters 29.6 (2025): 269.
Chicago
Yen, C., Chen, P. C., Chen, S., Wu, W., Yen, C., Lin, Y., Wu, P., Chen, C., Wang, J., Chao, T., Yang, M., Fletcher, J. A."Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma". Oncology Letters 29, no. 6 (2025): 269. https://doi.org/10.3892/ol.2025.15015
Copy and paste a formatted citation
x
Spandidos Publications style
Yen C, Chen PC, Chen S, Wu W, Yen C, Lin Y, Wu P, Chen C, Wang J, Chao T, Chao T, et al: Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma. Oncol Lett 29: 269, 2025.
APA
Yen, C., Chen, P.C., Chen, S., Wu, W., Yen, C., Lin, Y. ... Fletcher, J.A. (2025). Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma. Oncology Letters, 29, 269. https://doi.org/10.3892/ol.2025.15015
MLA
Yen, C., Chen, P. C., Chen, S., Wu, W., Yen, C., Lin, Y., Wu, P., Chen, C., Wang, J., Chao, T., Yang, M., Fletcher, J. A."Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma". Oncology Letters 29.6 (2025): 269.
Chicago
Yen, C., Chen, P. C., Chen, S., Wu, W., Yen, C., Lin, Y., Wu, P., Chen, C., Wang, J., Chao, T., Yang, M., Fletcher, J. A."Ferroptosis as a therapeutic vulnerability in MDM2 inhibition in dedifferentiated liposarcoma". Oncology Letters 29, no. 6 (2025): 269. https://doi.org/10.3892/ol.2025.15015
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