Anisomycin Activates Utrophin Upregulation Through a p38 Signaling Pathway

Abstract

Duchenne muscular dystrophy is a recessive X‐linked disease characterized by progressive muscle wasting; cardiac or respiratory failure causes death in most patients by the third decade. The disease is caused by mutations in the dystrophin gene that lead to a loss of functional dystrophin protein. Although there are currently few treatments for Duchenne muscular dystrophy, previous reports have shown that upregulating the dystrophin paralog utrophin in Duchenne muscular dystrophy mouse models is a promising therapeutic strategy. We conducted in silico mining of the Connectivity Map database for utrophin‐inducing agents, identifying the p38‐activating antibiotic anisomycin. Treatments of C2C12, undifferentiated murine myoblasts, and mdx primary myoblasts with anisomycin conferred increases in utrophin protein levels through p38 pathway activation. Anisomycin also induced utrophin protein levels in the diaphragm of mdx mice. Our study shows that repositioning small molecules such as anisomycin may prove to have Duchenne muscular dystrophy clinical utility.

Utrophin modulator drugs as potential therapies for Duchenne and Becker muscular dystrophies

“…In C2C12 muscle cells, it induces a 2.5‐fold increase in utrophin levels in vitro. It is also reported to significantly increase utrophin protein in the diaphragm of mdx mice treated daily with a low dose [ 71 ].…”

p38‐regulated FOXC1 stability is required for colorectal cancer metastasis

“…Similarly, p38 knockdown could also inhibit MMP10, SOX4 and SOX13 expression in HCT8 cells ( Figure 6C,D). We used anisomycin, a p38 activation inducer [25], to treat HCT8 cells and found that anisomycin activated the expression of FOXC1, which was then repressed by SB203580 in wildtype HCT8 cells ( Figure 6E). As anisomycin is also a JNK activator, we used JNK-specific inhibitor SP600125 to treat HCT8 cells together with anisomycin, but neither FOXC1 nor p38 expression was changed by SP600125 (see supplementary material, Figure 6D).…”