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Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma
Wang Yangyun1, Shi Guowei1, Shi Shufen2
1Department of Urology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, People's Republic of China.
Abstract:
Renal cell carcinoma (RCC) is a common type of urological cancer and is often diagnosed at an advanced stage. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is used as second-line therapy for sorafenib- or sunitinib-refractory metastatic RCC. However, the clinical benefits of Everolimus are often hampered by drug resistance. Ferroptosis is a novel form of regulated cell death that has recently been implicated in the development and therapeutic responses to different cancers. RSL3 ((1S,3R)-RSL3) and Erastin are two experimental compounds that can induce ferroptosis. In the present study, we evaluated the anti-tumor effects of Everolimus in combination with RSL3 or Erastin in RCC. Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in RCC cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Moreover, the forced expression of GPX4 abrogated ferroptosis induced by the combined treatment of Everolimus and RSL3/Erastin. Taken together, these results demonstrated that Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment and it may also help to overcome the limitation in clinical applicability of Everolimus.
Insights
Combining Everolimus with ferroptosis inducers RSL3 or Erastin shows synergistic anti-tumor effects in renal cell carcinoma (RCC). This approach may overcome Everolimus resistance, offering a promising new therapeutic strategy for advanced RCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Renal cell carcinoma (RCC) is a prevalent urological cancer often diagnosed at advanced stages.
- Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a second-line treatment for metastatic RCC but faces drug resistance challenges.
- Ferroptosis, a regulated cell death pathway, is increasingly recognized for its role in cancer development and treatment response.
Purpose of the Study:
- To investigate the anti-tumor efficacy of combining Everolimus with ferroptosis-inducing agents (RSL3 and Erastin) in renal cell carcinoma.
- To elucidate the underlying molecular mechanisms driving the synergistic effects of this combination therapy.
Main Methods:
- Evaluation of the combined anti-tumor effects of Everolimus with RSL3 or Erastin on RCC cell viability.
- Investigation of ferroptosis induction as a mechanism of cell death.
- Analysis of the mTOR-4EBP1 signaling pathway and the role of GPX4 in mediating the synergistic effects.
Main Results:
- Everolimus in combination with RSL3 or Erastin demonstrated synergistic inhibition of RCC cell viability.
- The combined treatment effectively induced ferroptosis in RCC cells.
- Inhibition of the mTOR-4EBP1 pathway was crucial for the synergistic anti-tumor activity.
- Overexpression of GPX4 counteracted the ferroptosis induced by the combination therapy.
Conclusions:
- The combination of Everolimus with RSL3 or Erastin presents a promising therapeutic strategy for renal cell carcinoma.
- This combination therapy has the potential to overcome Everolimus resistance and improve clinical outcomes in advanced RCC.
- Targeting ferroptosis alongside mTOR inhibition offers a novel approach for RCC treatment.
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