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APG-115 Induces SLC7A11-Mediated Ferroptosis and Upregulates PD-L1 Expression in Thyroid Cancer
Lei Liang1, Zhulan Chen1,2, Defeng Lei1
1Department of Nuclear Medicine, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen 518036, Guangdong, China.
Abstract:
The murine double minute 2 (MDM2)-p53 interaction inhibitor APG-115 demonstrates therapeutic potential in advanced malignancies. However, its molecular mechanism, especially for programmed death ligand 1 (PD-L1) immunotherapy modulation, remains poorly understood in thyroid cancer (TC). Herein, we conducted a series of in vitro and in vivo studies to investigate the therapeutic effect of APG-115 and the underlying molecular mechanisms in TC. We performed Cell Counting Kit (CCK-8) and cell scratch assay to assess the effect of APG-115 on the biological behavior of TC cells. Meanwhile, we performed animal experiments to investigate the therapeutic effect of APG-115 on TC in vivo. TC patient-derived organoids were further used to evaluate the potential value for clinical application of APG-115. Our results showed that APG-115 exhibited beneficial therapeutic effects in TC both in vitro and in vivo. Mechanistically, APG-115 restored the p53 antitumor effects by blocking MDM2-p53 binding and upregulating the PD-L1 expression. APG-115 downregulated Solute Carrier Family 7 Member 11 (SLC7A11) expression, contributing to lipid peroxidation and affecting PD-L1 expression in TC. Our study expands the clinical application value of APG-115 in cancer treatment, especially by further exploring the complex interplay between APG-115, PD-L1 immunotherapy, and ferroptosis.
Insights
The MDM2-p53 inhibitor APG-115 shows therapeutic promise in thyroid cancer (TC) by restoring p53 function and upregulating PD-L1 expression. This study reveals APG-115
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- The MDM2-p53 inhibitor APG-115 has shown potential in advanced cancers.
- Its precise mechanism in thyroid cancer (TC), particularly concerning PD-L1 immunotherapy, is not well understood.
- Understanding these mechanisms is crucial for optimizing cancer treatment strategies.
Purpose of the Study:
- To investigate the therapeutic efficacy of APG-115 in thyroid cancer (TC) both in vitro and in vivo.
- To elucidate the molecular mechanisms underlying APG-115's effects in TC, focusing on p53, PD-L1, and ferroptosis.
- To evaluate the potential clinical applicability of APG-115 in TC treatment.
Main Methods:
- In vitro studies using CCK-8 and cell scratch assays to assess APG-115's impact on TC cell behavior.
- In vivo animal experiments to evaluate the therapeutic effect of APG-115 in a TC model.
- Utilizing patient-derived organoids to assess the clinical potential of APG-115.
Main Results:
- APG-115 demonstrated significant therapeutic benefits in both in vitro and in vivo TC models.
- APG-115 reactivated p53 antitumor activity by inhibiting MDM2-p53 binding and increasing PD-L1 expression.
- APG-115 reduced SLC7A11 expression, inducing lipid peroxidation and influencing PD-L1 levels in TC.
Conclusions:
- APG-115 exhibits promising therapeutic effects for thyroid cancer.
- The study clarifies APG-115's role in modulating PD-L1 expression and its connection to ferroptosis in TC.
- These findings support the expanded clinical application of APG-115, particularly in combination with PD-L1 immunotherapy.
