Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
J Cancer Res Clin Oncol. 2013 Jul;139(7):1105-15. doi: 10.1007/s00432-013-1412-6. Epub 2013 Mar 28.
To evaluate the effect of proteasome inhibitor MG132 in cancer cachexia and to delineate the molecular mechanism underlying.
We established an experimental cancer cachexia model by subcutaneously implanting colon 26 cells into the armpits of BALB/c mice. Following administration of MG132 at various time points, body weight, food intake, gastrocnemius muscle weight, spontaneous activity and survival of tumor-bearing mice were examined along with tumor growth. Moreover, cachectic markers including glucose, triglyceride, albumin and total proteins as well as levels of the proinflammatory cytokines TNF-α and IL-6 in serum and gastrocnemius tissue were measured. Finally, mRNA and protein levels of p65, IκBα, and ubiquitin E3 ligases MuRF1 and MAFbx in gastrocnemius muscle were assessed.
MG132 treatment significantly alleviated cancer cachexia as demonstrated by attenuated weight loss, altered carbohydrate metabolism and muscle atrophy and increased spontaneous activity and survival time of tumor-bearing mice. MG132 reduced tumor growth and the levels of TNF-α and IL-6 in serum and gastrocnemius tissue. NF-κB, MuRF1 and MAFbx were also inhibited by MG132. Unexpectedly, MG132 was more efficient when administrated during the early stages of cachexia. MG132 had no effect on food intake of tumor-bearing mice.
Our results demonstrate that MG132-induced inhibition of the ubiquitin-proteasome pathway in cancer cachexia decreased the activity of NF-κB and the degradation of IκBα, and reduced the levels of TNF-α and IL-6 in serum and gastrocnemius tissue, accompanied by downregulation of MuRF1 and MAFbx. These data suggest that MG132 is a potential therapeutic and preventive agent for cancer cachexia.
评估蛋白酶体抑制剂 MG132 在癌症恶病质中的作用，并阐明其潜在的分子机制。
我们通过将结肠 26 细胞皮下植入 BALB/c 小鼠腋窝来建立实验性癌症恶病质模型。在给予 MG132 后的不同时间点，检查荷瘤小鼠的体重、食物摄入量、腓肠肌重量、自发活动和生存情况以及肿瘤生长情况。此外，还测量了血清和腓肠肌组织中的葡萄糖、甘油三酯、白蛋白和总蛋白等恶病质标志物以及促炎细胞因子 TNF-α 和 IL-6 的水平。最后，评估了腓肠肌中 p65、IκBα 和泛素 E3 连接酶 MuRF1 和 MAFbx 的 mRNA 和蛋白水平。
MG132 治疗显著减轻了癌症恶病质，表现为体重减轻减轻、碳水化合物代谢改变和肌肉萎缩以及自发活动增加和荷瘤小鼠的生存时间延长。MG132 减少了肿瘤生长以及血清和腓肠肌组织中 TNF-α 和 IL-6 的水平。NF-κB、MuRF1 和 MAFbx 也被 MG132 抑制。出乎意料的是，MG132 在恶病质早期给药时效果更好。MG132 对荷瘤小鼠的食物摄入量没有影响。
我们的结果表明，MG132 诱导的癌症恶病质中泛素-蛋白酶体途径的抑制降低了 NF-κB 的活性和 IκBα 的降解，并降低了血清和腓肠肌组织中 TNF-α 和 IL-6 的水平，同时下调了 MuRF1 和 MAFbx。这些数据表明，MG132 是癌症恶病质的一种有潜力的治疗和预防剂。
