Cancer-Induced Muscle Wasting Requires p38β MAPK Activation of p300

Area of Science:

• Molecular Biology
• Oncology
• Metabolic Syndrome

Background:

• Cancer-associated cachexia is a lethal metabolic syndrome with undefined causes and treatments.
• Previous research identified p300 as a mediator of cancer-induced muscle wasting via C/EBPβ activation.
• The signaling pathway activating p300 in cancer remains unknown.

Purpose of the Study:

• To elucidate the signaling mechanism that activates p300 in response to cancer.
• To identify p38β MAPK as a central mediator and potential therapeutic target for cancer-induced muscle wasting.
• To evaluate nilotinib as a selective inhibitor of p38β MAPK for treating cancer cachexia.

Main Methods:

• Investigated the role of Toll-like receptor 4 and p38β MAPK in cancer-induced muscle wasting.
• Utilized C2C12 myotubes to assess the impact of kinase inhibitors on muscle protein loss.
• Administered nilotinib to tumor-bearing mice to evaluate its efficacy in alleviating muscle wasting and prolonging survival.

Main Results:

• Cancer-induced Toll-like receptor 4 activation in skeletal muscle leads to p38β MAPK-mediated phosphorylation of p300 at Ser-12.
• This phosphorylation stimulates C/EBPβ acetylation, a necessary and sufficient step for muscle wasting.
• Nilotinib selectively inhibited p300 activation and prevented muscle protein loss in vitro, outperforming SB202190.
• Low-dose nilotinib treatment in mice alleviated muscle wasting and extended survival.

Conclusions:

• p38β MAPK is a critical mediator of cancer-induced muscle wasting through the p300/C/EBPβ pathway.
• Nilotinib, a selective p38β MAPK inhibitor, effectively ameliorates cancer cachexia in preclinical models.
• Nilotinib represents a promising therapeutic strategy for human cancer cachexia.