Dissecting the role of Hippo signaling in platinum-based chemotherapy

剖析 Hippo 信号在铂类化疗中的作用

• 批准号: 10311544
• 负责人: Wenqi Wang
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311544
• 关键词: Accounting; Address; Antibodies; Antineoplastic Agents; Apoptosis; Attenuated; Automobile Driving; Biological Models; Cadmium; Cancer cell line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemoresistance; Cisplatin; DNA Binding; Data; Defect; Drosophila genus; Drug Metabolic Detoxication; Drug resistance; Event; Functional disorder; Genetic Transcription; Growth; Health; Heavy Metals; Homeostasis; Human; Knock-out; Knowledge; LATS1 gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Metals; Molecular; Nuclear Translocation; Organ; Organ Size; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Platinum; Process; Publishing; Regulation; Research; Resistance; Resistance development; Role; Series; Signal Pathway; Signal Transduction; Solid Neoplasm; Stress; System; Techniques; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Toxic effect; Tumor Suppression; Zinc; base; cancer cell; cancer therapy; chemosensitizing agent; chemotherapy; human disease; in vivo; malignant breast neoplasm; metal poisoning; mutant; novel; nuclear factor 1; overexpression; reconstitution; refractory cancer; response; success; transcription factor; transcription factor MTF-1; tumor

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.

项目概要 以铂类为基础的化疗已广泛用于治疗多种实体瘤，包括乳腺癌、 肺癌和卵巢癌。最初的治疗成功是通过铂类化疗药物实现的，例如 顺铂；然而，许多肿瘤被发现具有内在耐药性或逐渐产生耐药性 顺铂治疗。这种耐药性极大地限制了它们的治疗潜力。值得注意的是，铂基 化合物是唯一用于癌症治疗的含有重金属的化疗药物，这导致 造成其抵抗力的独特机制。其中，细胞防御机制， 隔离、储存、运输和排出重金属，是此类铂基药物的支柱 反抗。因此，阐明重金属反应的调控不仅有助于确定关键参与者 推动人类癌症中的顺铂耐药性，同时也开发了化疗增敏方法 治疗患有顺铂耐药癌症的患者。 多个模型系统的研究已完全确立 Hippo 通路作为关键信号通路 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。河马途径 可以通过调节其下游效应子 YAP/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的顺铂耐药性有关， 而其根本机制尚不完全清楚。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，导致癌细胞对顺铂等铂类化疗药物产生耐药性。在这个 项目中，我们将阐明 Hippo 途径调节的重金属稳态在驱动顺铂中的作用 目标 1 中的耐药性，并测试 Hippo 途径是否可以用作顺铂的化学增敏剂 目标 2 中的相关化疗。