Cancer-Induced Muscle Wasting Requires p38β MAPK Activation of p300

Abstract

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/EBPbeta, 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 (TLR4) in skeletal muscle, p38beta MAPK phosphorylates Ser-12 on p300 to stimulate C/EBPbeta acetylation, which is necessary and sufficient to cause muscle wasting. Thus, p38beta MAPK is a central mediator and therapeutic target of cancer-induced muscle wasting. In addition, nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38beta MAPK, inhibited p300 activation 20-fold more potently than the p38alpha/beta MAPK inhibitor SB202190 and abrogated cancer cell-induced muscle protein loss in C2C12 myotubes without suppressing p38beta MAPK-dependent myogenesis. Systemic administration of nilotinib at a low dose (0.5 mg/kg/day, IP) 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 p38beta MAPK.