使用 p38α MAPK 抑制剂减少白色脂肪组织棕色化可改善磁共振成像评估的癌症相关性恶病质。
Reducing White Adipose Tissue Browning Using p38α MAPK Inhibitors Ameliorates Cancer-Associated Cachexia as Assessed by Magnetic Resonance Imaging.
机构信息
Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China.
Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30329, USA.
出版信息
Nutrients. 2022 Jul 22;14(15):3013. doi: 10.3390/nu14153013.
BACKGROUND
Up to 80% of pancreatic cancer patients suffer from cachexia. White adipose tissue (WAT) browning caused by the tumorigenicity and progression aggravates the cancer-associated cachexia (CAC). Cancer-initiated changes in the protein-38 mitogen-activated protein kinases (p38 MAPK) pathway are likely involved in the development of CAC.
METHODS
p38 MAPK inhibitors, VCP979 or SB203580, were used in the and models of pancreatic cancer cachexia. Expression of uncoupling protein 1 (UCP1) in the p38 MARK pathway and the properties and level of white adipocytes were analyzed and correlated to browning, followed by immunohistochemistry and Western blotting validations. Changes in the volume and fat fraction of WAT in animals were monitored by magnetic resonance imaging (MRI).
RESULTS
The size of white adipocytes was increased after being treated with the p38 MAPK inhibitors, along with increase in the MRI-measured volume and fat fraction of WAT. Comparing two p38 MAPK inhibitors, the p38α subunit-specific inhibitor VCP979 had a better therapeutic effect than SB203580, which targets both p38α and β subunits.
CONCLUSIONS
Blockade of p38 MAPK reduced the WAT browning that contributes to CAC. Thus, p38 MARK inhibitors can potentially be used as a therapy for treating CAC. Non-invasive MRI can also be applied to assess the progression and treatment responses of CAC.
背景
多达 80%的胰腺癌患者患有恶病质。肿瘤发生和进展引起的白色脂肪组织（WAT）褐变加剧了癌症相关的恶病质（CAC）。蛋白 38 丝裂原活化蛋白激酶（p38 MAPK）通路中癌症引发的变化可能参与 CAC 的发生。
方法
使用 p38 MAPK 抑制剂 VCP979 或 SB203580 处理胰腺癌恶病质的 和 模型。分析 p38 MAPK 通路中解偶联蛋白 1（UCP1）的表达以及白色脂肪细胞的特性和水平，并与褐变相关，随后进行免疫组织化学和 Western blot 验证。通过磁共振成像（MRI）监测动物 WAT 体积和脂肪分数的变化。
结果
用 p38 MAPK 抑制剂处理后，白色脂肪细胞的大小增加，同时 MRI 测量的 WAT 体积和脂肪分数增加。与两种 p38 MAPK 抑制剂相比，p38α 亚基特异性抑制剂 VCP979 比靶向 p38α 和β亚基的 SB203580 具有更好的治疗效果。
结论
阻断 p38 MAPK 减少了导致 CAC 的 WAT 褐变。因此，p38 MAPK 抑制剂可潜在地用作治疗 CAC 的方法。非侵入性 MRI 也可用于评估 CAC 的进展和治疗反应。
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