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Abstract
Introduction Radiotherapy is an important treatment for cervical cancer, but radioresistance remains the major obstacle during tumor treatment and is an important cause of recurrence or progression in patients with locally advanced cervical cancer.
Methods Two evolutionary radioresistant cell models were constructed by step irradiation. Molecular and metabolic changes during radioresistance were analyzed by RNA-sequencing and LC-MS non-targeted metabolomics. RNA-seq combined with ATAC-seq were applied to screen transcription factors regulating radiosensitivity. E2F7-mediated resistance was investigated both in vivo and in vitro, followed by validation on clinical samples. ChIP-seq combined with RNA-seq analysis were performed to find downstream target molecules of E2F7. Lipid metabolic inhibitors and unsaturated fatty acids were used to assess the sensitizing effect on radiotherapy.
Results In this study, we uncovered that metabolic reprogramming was the most significant change between radioresistant and radiosensitive cervical cancer. Fatty acid metabolic reprogramming, especially selective unsaturated fatty acid remodeling, gradually occurs during radioresistance. Compared with glycolysis inhibitors or glutamate metabolic inhibitors, fatty acid synthase inhibitors strongly enhanced ionizing radiation damage in radioresistant cells. Mechanically, progressively down-regulated E2F7 in cervical cancer cells reduced the transcriptional activation of ACSL4, which in turn, decreased the incorporation of polyunsaturated fatty acids into membrane lipids, thus promoting ferroptosis-dependent resistance to radiotherapy. Polyunsaturated fatty acid supplementation was found to be effective in synergizing radiotherapy.
Conclusion/Implications We highlight the role of lipid metabolic reprogramming in cervical cancer radioresistance and identify E2F7/ACSL4 signaling as critical for ferroptosis-dependent radiosensitivity. Additionally, we propose a new strategy for synergizing radiotherapy with lipid synthase inhibitors in cervical cancer.
