The multifunctional antitumor properties of Withaferin A (WA), the manifold studied bioactive compound of the plant Withania somnifera, have been well established in many different in vitro and in vivo cancer models. This undoubtedly has led to a much better insight in the underlying mechanisms of WAs broad antitumor activity range, but also raises additional challenging questions on how all these antitumor properties could be explained on a molecular level. Therefore, a lot of effort was made to characterize the cellular WA target proteins, since these binding events will lead and initiate the observed downstream effects. Based on a proteomic perspective, this review provides novel insights in the molecular chain of events by which WA potentially exercises its antitumor activities. We illustrate that WA triggers multiple cellular stress pathways such as the NRF2-mediated oxidative stress response, the heat shock response and protein translation events and at the same time inhibits these cellular protection mechanisms, driving stressed cancer cells towards a fatal state of collapse. If cancer cells manage to restore homeostasis and survive, a stress-independent WA antitumor response comes into play. These include the known inhibition of cytoskeleton proteins, NFκB pathway inhibition and cell cycle inhibition, among others. This review therefore provides a comprehensive overview which integrates the numerous WA–protein binding partners to formulate a general WA antitumor mechanism.

中文翻译：

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睡茄素 A 的广谱抗肿瘤特性：蛋白质组学视角

睡茄素 A (WA) 是睡茄植物中经过多方研究的生物活性化合物，其多功能抗肿瘤特性已在许多不同的体外和体内癌症模型中得到充分证实。这无疑使我们对WAs广泛的抗肿瘤活性范围的潜在机制有了更好的了解，但也提出了更多具有挑战性的问题，即如何在分子水平上解释所有这些抗肿瘤特性。因此，人们付出了大量的努力来表征细胞 WA 靶蛋白，因为这些结合事件将导致并启动观察到的下游效应。基于蛋白质组学的角度，这篇综述对 WA 潜在发挥其抗肿瘤活性的分子链事件提供了新的见解。我们证明WA触发多种细胞应激途径，例如NRF2介导的氧化应激反应、热休克反应和蛋白质翻译事件，同时抑制这些细胞保护机制，驱使受压的癌细胞走向致命的崩溃状态。如果癌细胞能够恢复体内平衡并存活下来，与应激无关的 WA 抗肿瘤反应就会发挥作用。其中包括已知的细胞骨架蛋白抑制、NFκB 通路抑制和细胞周期抑制等。因此，这篇综述提供了一个全面的概述，整合了众多的 WA 蛋白结合伙伴，以制定一般的 WA 抗肿瘤机制。