Abstract 397: Exploring the role of MDM2-TP53 pathway and ATM in regulation of ferroptosis in dedifferentiated liposarcoma
Authors: Yen Chueh-Chuan , Chen San-Chi , Chen Chih-Hsueh , Wang Jir-You , Chen Chao-Ming , Wu Po-Kuei , Yang Muh-Hwa , Chen Wei-Ming 
Published: March 2024

Background: Ferroptosis, a process involved in accumulation of lipid-based reactive oxygen species (ROS), is a form of cell death with unique morphologic features and regulatory mechanism. Tumor suppressor p53 (TP53) is a key factor in regulation of ferroptosis through multiple pathways. Mouse double minute 2 homolog (MDM2), a key oncogene of dedifferentiated LPS (DDLPS), is one of the negative regulators of the TP53. In our previous study, we had showed that nutlin-3, a MDM2 inhibitor, could exert synergistic cytotoxicity with ferroptosis-inducing agent (erastin and RSL3) on DDLPS in a sequential manner, possibly through upregulation of SLC3A2 with altered cystine/glutamate exchange (AACR Annual Meeting 2023 abstract#4777). Mutated in Ataxia-Telangiectasia gene (ATM) is a critical gene in DNA damage response. ATM could regulate ferroptosis either directly through altered iron pool, or indirectly through activating TP53 by phosphorylation of MDM2. In this study, we explored the role of ATM and MDM2-TP53 pathway, as well as interaction between them, in regulation of ferroptosis of DDLPS. We also studied the potential role of combination of DNA damaging agent (DDA), such as cisplatin, with ferroptosis-inducing agents in the treatment of DDLPS.

Methods: We explored the possible synergistically cytotoxic effect of cisplatin and ferroptosis-inducing agents in DDLPS cell lines. We also investigated the role of ATM in this synergistic effect by using siRNA or ATM inhibitor. In addition, we used cystine uptake assay (measurement of altered cystine/glutamate exchange) and iron level assay (measurement of labile iron pool) to study the functional change responsible to ferroptosis-inducing effect of cisplatin. Finally, we used immunoblotting study to reveal the potential molecular mechanism responsible for synergistic effect of cisplatin and ferroptosis-inducing agent.

Results: Cisplatin and erastin showed synergistic cytotoxicity in DDLPS cell line, most likely through ferroptosis-inducing effect. Cisplatin could activate ATM, with resultant dissociation of TP53 and MDM2. Cisplatin could exert ferroptosis-inducing effect through down-regulation SLC7A11A with resultant decrease cystine uptake, as well as increase labile iron pool. ATM inhibition could offset the ferroptosis-inducing effect of cisplatin by reversing both effects.

Conclusion: Modulation of ferroptosis is a potential treatment strategy in DDLPS. MDM2-TP53 pathway and ATM as well as interaction of both may play an important role in regulation of ferroptosis in DDLPS. Combination of DDA, such as cisplatin, and ferroptosis-inducing agents is a potential strategy in DDLPS treatment.

Citation Format: Chueh-Chuan Yen, San-Chi Chen, Chih-Hsueh Chen, Jir-You Wang, Chao-Ming Chen, Po-Kuei Wu, Muh-Hwa Yang, Wei-Ming Chen. Exploring the role of MDM2-TP53 pathway and ATM in regulation of ferroptosis in dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 397.