Cancer-related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction
Cancer-related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction
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DOI：
10.3892/ijmm.2019.4435
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发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Saligan, Leorey N.
中科院分区：
文献类型：
--
作者：
Feng, Li Rebekah;Wolff, Brian S.;Saligan, Leorey N.
雄激素剥夺疗法(ADT)联合放射治疗(RT)是非转移性前列腺癌(NMPC)的标准护理治疗。尽管有效，但与治疗相关的症状，包括疲劳，极大地降低了癌症患者的生活质量。本研究的目的是检测ADT/RT联合应用对疲劳的影响，并了解其潜在的机制。入选对象为患有NMPC的。使用癌症治疗功能评估--疲劳来评估疲劳。线粒体功能参数以从受试者全血中提取的外周血单核细胞(PBMC)的耗氧量来测量。建立了ADT/RT诱导的疲劳小鼠模型，通过减少54只小鼠的自愿车轮跑活动(VWRA)来测量疲劳。用葡萄糖转运蛋白4(GLUT4)和转录因子A，线粒体(TFAM)的蛋白质印迹分析评估ADT/RT小鼠脑内线粒体的功能。结果表明，与非ADT组相比，ADT组在RT过程中疲劳加剧。这种影响是疲劳所特有的，因为抑郁症状不受影响。与非疲劳受试者相比，疲劳受试者的PBMCs表现出较低的ATP偶联效率，这表明线粒体功能障碍。ADT/RT小鼠证实了ADT和RT在降低VWRA方面的协同作用。ADT/RT小鼠脑组织中GLUT4和TFAM水平降低，提示神经元代谢动态平衡受损可能参与疲劳的发病。综上所述，这些发现表明ADT/RT引起的疲劳可能与外周和中枢神经系统(CNS)的线粒体功能障碍有关。ADT/RT的协同作用在小鼠模型上是行为重现的，其机制可能与中枢神经系统的生物能量学有关。
Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. A total of 64 participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy-Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants' whole blood. An ADT/RT-induced fatigue mouse model was developed, with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using western blot analysis of glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). The results demonstrated that fatigue in the ADT group was exacerbated during RT compared with the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated the synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. In conclusion, these findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model and its mechanism may be related to bioenergetics in the CNS.