Cancer-Induced Muscle Wasting Requires p38β MAPK Activation of p300.

Autor:	Sin TK; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas., Zhang G; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas., Zhang Z; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas., Zhu JZ; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas., Zuo Y; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas., Frost JA; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas., Li M; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas.; The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, Texas.; Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma., Li YP; Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas. Yi-Ping.Li@uth.tmc.edu.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Feb 15; Vol. 81 (4), pp. 885-897. Date of Electronic Publication: 2020 Dec 22.
DOI:	10.1158/0008-5472.CAN-19-3219
Abstrakt:	Cancer-associated cachexia, characterized by muscle wasting, is a lethal metabolic syndrome without defined etiology or established treatment. We previously found that p300 mediates cancer-induced muscle wasting by activating C/EBPβ, which then upregulates key catabolic genes. However, the signaling mechanism that activates p300 in response to cancer is unknown. Here, we show that upon cancer-induced activation of Toll-like receptor 4 in skeletal muscle, p38β MAPK phosphorylates Ser-12 on p300 to stimulate C/EBPβ acetylation, which is necessary and sufficient to cause muscle wasting. Thus, p38β MAPK is a central mediator and therapeutic target of cancer-induced muscle wasting. In addition, nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38β MAPK, inhibited p300 activation 20-fold more potently than the p38α/β MAPK inhibitor, SB202190, and abrogated cancer cell-induced muscle protein loss in C2C12 myotubes without suppressing p38α MAPK-dependent myogenesis. Systemic administration of nilotinib at a low dose (0.5 mg/kg/day, i.p.) in tumor-bearing mice not only alleviated muscle wasting, but also prolonged survival. Therefore, nilotinib appears to be a promising treatment for human cancer cachexia due to its selective inhibition of p38β MAPK. SIGNIFICANCE: These findings demonstrate that prevention of p38β MAPK-mediated activation of p300 by the FDA-approved kinase inhibitor, nilotinib, ameliorates cancer cachexia, representing a potential therapeutic strategy against this syndrome. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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