Abstract
Upregulation of ubiquitin ligase atrogin1/MAFbx and muscle wasting are hallmarks of cancer cachexia; however, the underlying mechanism is undefined. Here, we describe a novel signalling pathway through which Lewis lung carcinoma (LLC) induces atrogin1/MAFbx upregulation and muscle wasting. C2C12 myotubes treated with LLC-conditioned medium (LCM) rapidly activates p38 MAPK and AKT while inactivating FoxO1/3, resulting in atrogin1/MAFbx upregulation, myosin heavy chain loss, and myotube atrophy. The p38α/β MAPK inhibitor SB202190 blocks the catabolic effects. Upon activation, p38 associates with C/EBPβ resulting in its phosphorylation and binding to a C/EBPβ-responsive cis-element in the atrogin1/MAFbx gene promoter. The promoter activity is stimulated by LCM via p38β-mediated activation of the C/EBPβ-responsive cis-element, independent of the adjacent FoxO1/3-responsive cis-elements in the promoter. In addition, p38 activation is observed in the muscle of LLC tumour-bearing mice, and SB202190 administration blocks atrogin1/MAFbx upregulation and muscle protein loss. Furthermore, C/EBPβ(-/-) mice are resistant to LLC tumour-induced atrogin1/MAFbx upregulation and muscle wasting. Therefore, activation of the p38β MAPK-C/EBPβ signalling pathway appears a key component of the pathogenesis of LLC tumour-induced cachexia.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cachexia / genetics
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Cachexia / metabolism
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Carcinoma, Lewis Lung / genetics
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Carcinoma, Lewis Lung / metabolism*
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Cell Line
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Enzyme Inhibitors / metabolism
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism
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Imidazoles / metabolism
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Muscle Fibers, Skeletal / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Muscular Atrophy / metabolism
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Myosin Heavy Chains / metabolism
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / metabolism
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism*
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Signal Transduction
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Ubiquitin-Protein Ligases / metabolism*
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Enzyme Inhibitors
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Foxo1 protein, mouse
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Imidazoles
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Muscle Proteins
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Pyridines
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Fbxo32 protein, mouse
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SKP Cullin F-Box Protein Ligases
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Ubiquitin-Protein Ligases
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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Myosin Heavy Chains
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole