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Polyamine Depletion by D, L-alpha-difluoromethylornithine Inhibits Ewing Sarcoma Metastasis by Inducing Ferroptosis
Abstract:
Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in Ewing sarcoma. Here, we show that blocking polyamine synthesis with D, L-alpha-difluoromethylornithine (DFMO) causes a G1 cell cycle arrest, dose-dependent decreases in sarcosphere formation from Ewing sarcoma cell lines growing in non-adherent conditions and a decrease in clonogenic growth in soft agar. Further, we utilized our orthotopic implantation/amputation model of Ewing sarcoma metastasis to demonstrate that DFMO slowed primary tumor growth in addition to limiting metastasis. RNA sequencing demonstrated gene expression patterns consistent with induction of ferroptosis caused by polyamine depletion. Induction of ferroptosis was validated in vitro by demonstrating that ferrostatin-1, an inhibitor of ferroptosis, allows sphere formation even in the presence of DFMO. Collectively, these results reveal a novel mechanism by which DFMO prevents metastasis - induction of ferroptosis due to polyamine depletion. Our results provide preclinical justification to test the ability of DFMO to prevent metastatic recurrence in Ewing sarcoma patients at high risk for relapse.
Insights
D, L-alpha-difluoromethylornithine (DFMO) inhibits Ewing sarcoma growth and metastasis by depleting polyamines, inducing cell death via ferroptosis. This finding supports DFMO as a potential therapy to prevent cancer recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Polyamine metabolism is crucial in various cancers.
- Its role in Ewing sarcoma remained uninvestigated.
- Ewing sarcoma is an aggressive bone cancer with high metastatic potential.
Purpose of the Study:
- To investigate the role of polyamine metabolism in Ewing sarcoma.
- To evaluate the therapeutic potential of DFMO in Ewing sarcoma.
- To elucidate the mechanism of DFMO's anti-cancer effects.
Main Methods:
- Cell cycle analysis and clonogenic assays.
- Orthotopic implantation/amputation model for metastasis studies.
- RNA sequencing and ferroptosis inhibition assays.
Main Results:
- DFMO induced G1 cell cycle arrest and reduced tumor cell growth and sphere formation.
- DFMO treatment slowed primary tumor growth and limited metastasis in vivo.
- Polyamine depletion by DFMO induced ferroptosis, which was reversible with ferrostatin-1.
Conclusions:
- DFMO effectively inhibits Ewing sarcoma progression and metastasis through polyamine depletion and ferroptosis induction.
- DFMO presents a promising therapeutic strategy to prevent metastatic recurrence in high-risk Ewing sarcoma patients.
- Further clinical investigation of DFMO is warranted for Ewing sarcoma treatment.
