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: 9437762
• 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/9437762
• 关键词: Affect; Animal Model; Biguanides; Biological Models; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Treatment; Breast Cancer therapy; Cancer Etiology; Cell Line; Cell Proliferation; Cells; Cellular Metabolic Process; Cessation of life; Chromosomes; Clinical; Clinical Trials; Data; Development; Disease; Drug usage; ERBB2 gene; Energy Metabolism; FRAP1 gene; Feedback; Genes; Growth; Light; Malignant Neoplasms; Mammary Neoplasms; Maps; Metabolic; Metabolic stress; Metabolism; Metformin; Modeling; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Proteins; Regulation; Reporting; Role; STK11 gene; Sampling; TP53 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（由申请人提供）：乳腺癌是最常见的癌症，也是女性癌症死亡的第二大原因。更好地了解乳腺癌病因将有助于我们更好地预防和治疗这种疾病。 LBK1-AMPK 通路是能量代谢的核心调节因子，该通路的失调与癌症（包括乳腺癌）有关。二甲双胍等间接 AMPK 激活剂在乳腺癌预防和治疗中显示出有益作用。然而，除了 LKB1 突变之外，该通路在乳腺癌中如何被错误调节仍不清楚。在此应用中，基于我们广泛的初步数据，我们建议根据新确定的 AMPK 调节作用以及乳腺癌和治疗反应中的作用来表征几个因素。第一个因子称为肿瘤抑制蛋白 52 (TPD52)，我们发现它可以负向调节 AMPK。已知 TPD52 在 HER2+ 乳腺癌中过度表达，并与 HER2 一起促进肿瘤生长。 AMPK 通路也参与抗 HER2 反应。此外，我们发现 AMPK 调节 USP10。 USP10可以增强两种重要的肿瘤抑制因子p53和SIRT6的稳定性，因此我们的发现建立了一条新的AMPK下游途径。据悉，SIRT6还可以激活AMPK。因此，我们确定了AMPK调节的新轴，TPD52与AMPK下游因子UPS10/SIRT6负向调节AMPK，形成正反馈环，进一步激活AMPK，所有这些对于能量代谢和对二甲双胍引起的代谢应激的反应都非常重要。二甲双胍的反应是异质的；因此，我们的研究结果可以揭示潜在的机制。我们的初步数据表明，TPD52 过表达的细胞对二甲双胍以及二甲双胍+HER2 联合抑制剂更敏感。这与之前的研究一致，表明二甲双胍可以抑制细胞增殖并提高 HER2+ 乳腺癌患者的生存率。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通过负向调节AMPK，可以促进能量代谢失调并促进乳腺癌的发展。二甲双胍等药物对 TPD52 过度表达的患者更有效，并且可能与 HER2 抑制剂联合用于治疗 HER2+ 癌症。因此，在本申请中，我们建议使用细胞系、乳腺肿瘤样本和乳腺癌患者来源的异种移植物来确定TPD52如何调节AMPK通路以及AMPK如何通过USP10的调节来调节SIRT6和p53，以及这种调节对双胍和抗HER2治疗反应的影响。总之，这些研究将帮助我们了解这个新轴 TPD52-AMPK-USP10-SIRT6/p53 如何促进肿瘤发生和治疗反应。