title: MG132-mediated inhibition of the ubiquitin-proteasome pathway ameliorates cancer cachexia.
abstract: OBJECTIVE
  To evaluate the effect of proteasome inhibitor MG132 in cancer cachexia and to delineate the molecular mechanism underlying.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
authors.forename: Liuping
authors.initials: L
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.forename: Yao
authors.initials: Y
authors.lastname: Kou
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Yueyong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhou
authors.forename: Liangbin
authors.initials: L
authors.lastname: Jin
mesh_terms: D000230:Adenocarcinoma / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D050260:Carbohydrate Metabolism / Q000187:drug effects; D045744:Cell Line, Tumor; D015850:Interleukin-6 / Q000097:blood; D007976:Leupeptins / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D059748:Proteolysis; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D054875:Ubiquitination; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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