Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.
Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
Cancer Res. 2022 Dec 16;82(24):4515-4527. doi: 10.1158/0008-5472.CAN-21-4369.
Obesity induces numerous physiological changes that can impact cancer risk and patient response to therapy. Obese patients with cervical cancer have been reported to have superior outcomes following chemoradiotherapy, suggesting that free fatty acids (FFA) might enhance response to radiotherapy. Here, using preclinical models, we show that monounsaturated and diunsaturated FFAs (uFFA) radiosensitize cervical cancer through a novel p53-dependent mechanism. UFFAs signaled through PPARγ and p53 to promote lipid uptake, storage, and metabolism after radiotherapy. Stable isotope labeling confirmed that cervical cancer cells increase both catabolic and anabolic oleate metabolism in response to radiotherapy, with associated increases in dependence on mitochondrial fatty acid oxidation for survival. In vivo, supplementation with exogenous oleate suppressed tumor growth in xenografts after radiotherapy, an effect that could be partially mimicked in tumors from high fat diet-induced obese mice. These results suggest that supplementation with uFFAs may improve tumor responses to radiotherapy, particularly in p53 wild-type tumors.
Metabolism of monounsaturated and diunsaturated fatty acids improves the efficacy of radiotherapy in cancer through modulation of p53 activity. See related commentary by Jungles and Green, p. 4513.
肥胖会引起许多生理变化，这些变化可能会影响癌症风险和患者对治疗的反应。有报道称，肥胖的宫颈癌患者在接受放化疗后效果更好，这表明游离脂肪酸（FFA）可能增强对放疗的反应。在这里，我们使用临床前模型表明，单不饱和和双不饱和脂肪酸（uFFA）通过一种新的 p53 依赖性机制使宫颈癌放射敏感。uFFA 通过 PPARγ 和 p53 发出信号，在放疗后促进脂质摄取、储存和代谢。稳定同位素标记证实，宫颈癌细胞在放疗后增加了代谢分解和合成油酸的代谢，同时增加了对线粒体脂肪酸氧化的依赖以维持生存。在体内，外源性油酸补充在放疗后抑制异种移植瘤的生长，这一效应在高脂肪饮食诱导的肥胖小鼠的肿瘤中部分模拟。这些结果表明，补充单不饱和和双不饱和脂肪酸可能会提高癌症对放疗的反应，尤其是在野生型 p53 肿瘤中。
通过调节 p53 活性，单不饱和和双不饱和脂肪酸的代谢改善了癌症放疗的疗效。见 Jungles 和 Green 的相关评论，第 4513 页。
