Dissecting the role of Hippo signaling in platinum-based chemotherapy

项目摘要 以铂为基础的化疗已被广泛用于治疗各种实体瘤， 肺癌和卵巢癌最初的治疗成功是通过铂类化学药物实现的， 顺铂;然而，发现许多肿瘤对顺铂具有内在抗性或逐渐产生抗性。 顺铂治疗。这种抗性极大地限制了它们的治疗潜力。值得注意的是， 化合物是应用于癌症治疗的唯一含重金属的化学药物， 独特的机制解释了它们的抵抗力。其中，细胞防御机制， 螯合，储存，运输和排出重金属，代表了这种铂基药物的主要成分 阻力因此，阐明重金属反应的调控不仅有助于确定关键参与者， 在人类癌症中驱动顺铂耐药性，但也开发了化疗增敏方法， 治疗患有顺铂抗性癌症的患者。 来自多个模型系统的研究已经完全确立了Hippo途径作为关键信号传导途径， 通过限制细胞增殖和刺激细胞凋亡来控制器官和组织的大小。Hippo途径 可以通过调节其下游效应子雅普/TAZ来感知生长条件并控制细胞增殖。 值得注意的是，Hippo通路的失调与人类癌症中的顺铂耐药性有关， 而根本的机制还不完全清楚。有趣的是，我们的初步研究表明，河马 信号传导缺陷可以促进能够增加重金属流出的基因的转录， 中和，导致癌细胞对基于铂的化学药物如顺铂的抗性。在这 项目，我们将阐明海马途径调节的重金属稳态在驱动顺铂中的作用 目的1中的耐药性，并测试Hippo途径是否可用作顺铂的化学增敏剂。 目标2中的相关化疗。

PROJECT SUMMARY The platinum-based chemotherapy has been widely used for treating a variety of solid tumors including breast, lung and ovarian cancers. Initial therapeutic success is achieved by the platinum-based chemo-drugs like cisplatin; however, a number of tumors are found to be intrinsically resistant or gradually develop resistance to cisplatin treatment. This resistance greatly limits their therapeutic potential. Notably, the platinum-based compounds are the only heavy metal containing chemo-drugs applied to cancer treatment, which results in unique mechanisms accounting for their resistance. Of them, the cellular defensive machinery, which sequesters, stores, transports and expels heavy metals, represents a mainstay of such platinum-based drug resistance. Therefore, elucidating the regulation of heavy metal response will help not only identify key players that drives cisplatin resistance in human cancers, but also develop chemo-sensitizing approaches for the treatment of patients suffered from the cisplatin-resistant cancers. Studies from multiple model systems have fully established the Hippo pathway as a key signaling pathway that controls organ and tissue size via restricting cell proliferation and stimulating cell apoptosis. The Hippo pathway can sense growth conditions and control cell proliferation by modulating its downstream effectors YAP/TAZ. Notably, deregulation of the Hippo pathway has been connected with cisplatin resistance in human cancers, while the underlying mechanism is not fully understood. Interestingly, our preliminary studies revealed that Hippo signaling deficiency can promote the transcription of genes that are able to increase heavy metal efflux and neutralization, resulting in the cancer cell resistance to the platinum-based chemo-drugs like cisplatin. In this project, we will elucidate the role of the Hippo pathway-regulated heavy metal homeostasis in driving cisplatin resistance in Aim 1, and test whether the Hippo pathway can be employed as a chemo-sensitizer for the cisplatin- related chemotherapy in Aim 2.