Investigate the role of TPD52-AMPK pathway in tumorigenesis and cancer therapy

研究TPD52-AMPK通路在肿瘤发生和癌症治疗中的作用

• 批准号: 9101191
• 负责人: Liewei Wang
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101191
• 关键词: Affect; Animal Model; Biguanides; Biological Models; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; Cancer Etiology; Cell Line; Cell Proliferation; Cells; Cellular Metabolic Process; Cessation of life; Chromosome Mapping; Chromosomes; Clinical; Clinical Trials; Data; Development; Disease; Drug usage; ERBB2 gene; Energy Metabolism; FRAP1 gene; Feedback; Growth; Light; Malignant Neoplasms; Mammary Neoplasms; Metabolic; Metabolic stress; Metabolism; Metformin; Modeling; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Protein p53; Proteins; Regulation; Reporting; Role; STK11 gene; Sampling; Second Primary Cancers; TP53 gene; TPD52 gene; Testing; Therapeutic; Tumor Suppressor Proteins; Tumor Tissue; Woman; Xenograft procedure; base; breast tumorigenesis; cancer therapy; cell transformation; inhibitor/antagonist; malignant breast neoplasm; novel; outcome forecast; overexpression; personalized medicine; prevent; prospective; public health relevance; response; treatment response; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): Breast cancer is the most common cancer and the second leading cause of cancer death in women. A better understanding of breast cancer etiology would help us to better prevent and treat this disease. The LBK1-AMPK pathway is a central regulator of energy metabolism, and misregulation of this pathway has been implicated in cancers, including breast cancer. Indirect AMPK activators such as metformin have shown beneficial effect in breast cancer prevention and treatment. However, other than LKB1 mutations, how this pathway might be misregulated in breast cancer remains unclear. In this application, based on our extensive Preliminary Data, we propose to characterize several factors based on their newly identified roles in AMPK regulation and in turn, on breast cancer and treatment response. The first factor is called tumor suppressor protein 52 (TPD52) which we found to negatively regulate AMPK. TPD52 is known to overexpress in HER2+ breast cancer and, together with HER2, to promote tumor growth. The AMPK pathway is also known to be involved in anti-HER2 response. Furthermore, we found that AMPK regulates USP10. USP10 can enhance the stability of two important tumor suppressors, p53 and SIRT6, so our finding has established a new downstream pathway to AMPK. It is reported that SIRT6 can also activate AMPK. Therefore, we have identified a new axis of AMPK regulation with TPD52 negatively regulating AMPK with the AMPK downstream factors, UPS10/SIRT6 forming a positive feedback loop, further activating AMPK, all of which would be important in energy metabolism and response to metabolic stress induced by metformin. Metformin response is heterogeneous; therefore our findings could shed light on the underlying mechanisms. Our preliminary data indicated that cells with TPD52 overexpression were more sensitive to metformin as well as combined metformin+HER2 inhibitors. This is consistent with previous studies indicating that metformin can inhibit cell proliferation and increase patient survival in HER2+ breast cancer. Based on these preliminary findings, we hypothesize that the AMPK-USP10 axis contributes to the metabolic function of AMPK; TPD52, by negatively regulating AMPK, can promote misregulation of energy metabolism and contribute to breast cancer development. Drugs like metformin would be more effective in patients with TPD52 overexpression and might be used in combination with HER2 inhibitors in HER2+ cancers. Therefore, in this application, we propose to determine how TPD52 regulates the AMPK pathway and how AMPK might regulate SIRT6 and p53 through the regulation of USP10 as well as the impact of this regulation on response to biguanides and anti-HER2 therapy using cell lines, breast tumor samples, and breast cancer patient derived xenografts. In summary, these studies would help us to understand how this new axis TPD52-AMPK-USP10-SIRT6/p53 contributes to tumorigenesis and treatment response.

 描述（由适用提供）：乳腺癌是最常见的癌症，也是女性癌症死亡的第二大原因。更好地了解乳腺癌的病因将有助于我们更好地预防和治疗这种疾病。 LBK1-AMPK途径是能量代谢的核心调节剂，在包括乳腺癌在内的癌症中，这种途径的正调已被浸渍。间接AMPK激活剂（例如二甲双胍）在预防乳腺癌和治疗中表现出有益的作用。但是，除了LKB1突变之外，该途径在乳腺癌中如何被误导尚不清楚。在此应用中，根据我们广泛的初步数据，我们建议根据它们在AMPK调节中的新作用以及在乳腺癌和治疗反应中的新作用来表征几个因素。第一个因素称为肿瘤抑制蛋白52（TPD52），我们发现它对AMPK负调节。已知TPD52在HER2+乳腺癌中过表达，并与HER2一起促进肿瘤生长。已知AMPK途径也参与抗HER2响应。此外，我们发现AMPK调节USP10。 USP10可以增强两种重要的肿瘤补充剂P53和SIRT6的稳定性，因此我们的发现已经建立了通往AMPK的新下游途径。据报道，SIRT6也可以激活AMPK。因此，我们已经确定了一个新的AMPK调节轴，TPD52用AMPK下游因子负面控制AMPK，UPS10/SIRT6形成正反馈循环，进一步激活AMPK，所有这些在能量代谢中都很重要，并且对甲甲型代谢胁迫的响应对甲甲型的代谢应力很重要。二甲双胍反应是异质的；因此，我们的发现可以阐明基本机制。我们的初步数据表明，具有TPD52过表达的细胞对二甲双胍以及二甲双胍+HER2抑制剂的组合更敏感。这与以前的研究一致，表明二甲双胍可以抑制细胞增殖并增加HER2+乳腺癌的患者存活率。基于这些初步发现，我们假设AMPK-USP10轴有助于AMPK的代谢功能。 TPD52通过受负调节的AMPK可以促进能量代谢的不正调，并有助于乳腺癌的发展。像二甲双胍之类的药物在TPD52过表达的患者中会更有效，并且可以与HER2+癌症中的HER2抑制剂结合使用。因此，在此应用中，我们建议确定TPD52如何调节AMPK途径，以及AMPK如何通过调节USP10调节SIRT6和P53，以及该调节对使用细胞，乳腺癌样品以及乳腺癌患者衍生的Xenerived Xenemographications对Biguanides和Anti-Her2治疗的影响。总而言之，这些研究将帮助我们了解这种新的TPD52-AMPK-USP10-SIRT6/p53如何有助于肿瘤发生和治疗反应。