American Association for Cancer Research
00085472can193219-sup-230663_2_supp_6786117_qlch0k.docx (14.38 MB)

Supplementary Data from Cancer-Induced Muscle Wasting Requires p38β MAPK Activation of p300

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journal contribution
posted on 2023-03-31, 03:40 authored by Thomas K. Sin, Guohua Zhang, Zicheng Zhang, James Z. Zhu, Yan Zuo, Jeffrey A. Frost, Min Li, Yi-Ping Li

Supplementary figures


National Institute of Arthritis and Musculoskeletal and Skin Diseases




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. 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.

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