The role of AMPK and CD36 in breast cancer tumorigenesis and metastasis

AMPK和CD36在乳腺癌肿瘤发生和转移中的作用

• 批准号: 10377328
• 负责人: Nissim Hay
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377328
• 关键词: Acetyl-CoA Carboxylase; Address; Antioxidants; Applications Grants; Atherosclerosis; Attenuated; Blood Circulation; Brain; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Cancer cell line; Breast cancer metastasis; CD36 gene; Cancer Patient; Cause of Death; Cell Death; Cell Survival; Cell membrane; Cells; Consumption; Data; Development; Disease; Distant; Doxycycline; Extravasation; Fatty Acids; Glucose; Homeostasis; Human; Impairment; Implant; In Vitro; Knock-out; Knockout Mice; Lead; MDA MB 231; Malignant Neoplasms; Mammary gland; Mediating; Metabolic; Metabolism; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Metastatic to; Morbidity - disease rate; Mouse Mammary Tumor Virus; Mus; NADP; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Outcome; Pathway interactions; Pentosephosphate Pathway; Pharmacotherapy; Phosphorylation; Phosphorylation Inhibition; Population; Primary Neoplasm; Process; Publications; Reactive Oxygen Species; Rest; Role; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Therapeutic; Time; Tissues; Transplantation; Tumor stage; Tumorigenicity; Veterans; Woman; bone; cancer cell; cancer type; combat; fatty acid oxidation; glucose uptake; high risk; in vivo; inhibitor; long chain fatty acid; malignant breast neoplasm; military women; mortality; mouse model; neoplastic cell; obese patients; targeted cancer therapy; translational impact; translocase; tumor; tumor initiation; tumorigenesis; tumorigenic

Breast cancer is the most frequently occurring cancer in women. Military women are at increased risk of breast cancer. The mortality and morbidity from breast cancer is due to its metastatic spread. The role of AMPK in tumorigenesis is controversial. Although AMPK inhibition was implicated in promoting tumorigenesis, we showed, several years ago, that AMPK activation is required for tumor cells survival during solid tumor formation. In recent years this assertion was independently corroborated by others in various types of cancer. In this grant application we propose that AMPK and its downstream effector the fatty acid translocase, CD36, are required for breast cancer metastasis. It is known that high ROS levels in disseminating cells is an impediment for metastasis and therefore the metabolic rewiring of key signaling pathways is critical to confer enhanced antioxidant metabolism to overcome this hurdle. Combating high ROS levels during metastatic colonization requires increased glucose uptake and utilization. We propose that the excess of ROS levels in disseminating breast cancer cells is a consequence of impaired glucose uptake and utilization. This impairment inhibits the oxidative pentose phosphate pathway (oxPPP) that generates NADPH to combat ROS. The limited glucose utilization during dissemination also leads to the activation of AMPK. By inhibiting fatty acid synthesis (FAS) and by elevating fatty acid oxidation (FAO), AMPK could maintain intracellular NADPH levels to combat ROS even when glucose utilization is impaired. In the first part of this grant application we will delineate the mechanism by which AMPK activation is required for breast cancer metastasis. In the second part of the grant application we will determine if the fatty acid translocase, CD36, is required for tumorigenesis and metastasis mediated by AMPK activation, and whether CD36 could be systemically targeted to inhibit breast cancer metastasis. We will use human breast cancer cell lines and PDOs and orthotopic transplantation as well as a mouse models for breast cancer metastasis in these studies. The proposed studies have a translational impact as they will determine whether drug therapy that activates AMPK directly or indirectly could have worse outcomes with respect to breast cancer metastasis, and whether targeting CD36 could inhibit breast cancer metastasis particularly in obese patients.

乳腺癌是女性最常见的癌症。女性军人面临的风险增加 乳腺癌乳腺癌的死亡率和发病率是由于其转移扩散。的作用 AMPK在肿瘤发生中的作用存在争议。尽管AMPK抑制与促进 几年前，我们发现AMPK激活是肿瘤细胞存活所必需的， 在实体瘤形成期间。近年来，这一说法得到了其他人的独立证实， 各种癌症。在这项授权申请中，我们提出AMPK及其下游效应物， 脂肪酸移位酶CD36是乳腺癌转移所必需的。众所周知，高活性氧水平 是转移的障碍，因此，关键的代谢重新布线， 信号通路对于增强抗氧化剂代谢以克服这一障碍是至关重要的。 在转移性定殖期间对抗高ROS水平需要增加葡萄糖摄取， 利用率我们认为，在乳腺癌细胞的扩散中，ROS水平的过度是一个重要的因素。 葡萄糖摄取和利用受损的后果。这种损伤抑制氧化戊糖 磷酸途径（oxPPP），产生NADPH以对抗ROS。有限的葡萄糖利用 在传播过程中也导致AMPK的激活。通过抑制脂肪酸合成（FAS）， AMPK通过升高脂肪酸氧化（FAO），维持细胞内NADPH水平，对抗ROS 即使当葡萄糖利用受损时。在本补助金申请的第一部分，我们将描述 AMPK激活是乳腺癌转移所必需的机制。第二部分 我们将确定脂肪酸移位酶CD36是否是肿瘤发生所必需的， AMPK激活介导的转移，以及CD36是否可以全身靶向抑制 乳腺癌转移我们将使用人类乳腺癌细胞系和PDO， 移植以及小鼠模型的乳腺癌转移。拟议 研究具有转化影响，因为它们将确定激活AMPK的药物治疗是否 直接或间接的乳腺癌转移可能会有更糟糕的结果， 靶向CD36可以抑制乳腺癌转移，特别是在肥胖患者中。