Withaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass.
Withaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass.
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Withaferin A与卵巢癌拮抗调节骨骼肌质量。
DOI：
10.3389/fcell.2021.636498
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发表时间：
2021
影响因子：
5.5
通讯作者：
Kakar SS
中科院分区：
文献类型：
--
作者：
Straughn AR;Kelm NQ;Kakar SS
恶病质是一种复杂的消耗综合征，其压倒性地影响大多数晚期癌症患者。此外，目前没有有效的治疗剂来治疗由癌症诱导的肌肉萎缩。虽然一些临床前研究已经调查了恶病质的分子信号，但关于卵巢癌和相关恶病质的信息很少。我们实验室的工作最近表明，甾体内酯Withaferin A（WFA）能够在临床前小鼠模型中减弱卵巢癌的萎缩作用。然而，WFA的作用是否与其抗肿瘤特性有关，或者它是否能够直接靶向骨骼肌，还有待确定。本研究的目的是揭示WFA是否能够在无肿瘤和荷瘤条件下调节肌肉质量。WFA治疗可改善荷瘤和初治条件下的功能性肌肉力量和质量。观察到WFA和卵巢癌对关键的骨骼肌调节系统，特别是肌原祖细胞和蛋白水解降解途径起拮抗作用。我们的研究结果首次表明，虽然WFA具有抗肿瘤特性，但它也对骨骼肌质量产生肥大作用，这表明它可能是卵巢癌背景下的抗恶病质剂。
Cachexia is a complex wasting syndrome that overwhelmingly affects the majority of late-stage cancer patients. Additionally, there are currently no efficacious therapeutic agents to treat the muscle atrophy induced by the cancer. While several preclinical studies have investigated the molecular signals orchestrating cachexia, very little information exists pertaining to ovarian cancer and the associated cachexia. Work from our lab has recently demonstrated that the steroidal lactone Withaferin A (WFA) is capable of attenuating the atrophying effects of ovarian cancer in a preclinical mouse model. However, it remained to be determined whether WFA’s effect was in response to its anti-tumorigenic properties, or if it was capable of targeting skeletal muscle directly. The purpose of this study was to uncover whether WFA was capable of regulating muscle mass under tumor-free and tumor-bearing conditions. Treatment with WFA led to an improvement in functional muscle strength and mass under tumor-bearing and naïve conditions. WFA and ovarian cancer were observed to act antagonistically upon critical skeletal muscle regulatory systems, notably myogenic progenitors and proteolytic degradation pathways. Our results demonstrated for the first time that, while WFA has anti-tumorigenic properties, it also exerts hypertrophying effects on skeletal muscle mass, suggesting that it could be an anti-cachectic agent in the settings of ovarian cancer.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
12.4
作者：
Dittman, Jessica;Haydn, Tinka;Fulda, Simone
通讯作者：
Fulda, Simone
影响因子：
5.6
作者：
Bohnert KR;McMillan JD;Kumar A
通讯作者：
Kumar A
影响因子：
50.3
作者：
Acharyya, S;Butchbach, MER;Guttridge, DC
通讯作者：
Guttridge, DC
影响因子：
2.2
作者：
Damrauer JS;Stadler ME;Acharyya S;Baldwin AS;Couch ME;Guttridge DC
通讯作者：
Guttridge DC