Cancer-induced Muscle Wasting is IKK-dependent and NF-kappaB-independent

Existing data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-B transcription factors that regulate wasting is far from complete. In muscles of C26 tumor bearing mice, overexpression of d.n. IKK blocked muscle wasting by 69%, the IB-super repressor blocked wasting by 41%. In contrast, overexpression of d.n. IKK or d.n. NIK did not block C26-induced wasting. Surprisingly, overexpression of d.n. p65 or d.n. c-Rel did not significantly block muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-B transcription factors, we compared genome-wide p65 or p50 binding to DNA in control and cachectic muscle using ChIP-sequencing. Bioinformatic analysis of ChIP-seq data from control and C26 muscles showed increased p65 and p50 binding to a few regulatory and structural genes but only two of these genes were upregulated with atrophy. The p65 and p50 ChIP-seq data are consistent with our finding of no significant change in protein binding to an NF-B oligo in a gel shift assay. Taken together, these data support the idea that although inhibition of IB, and particularly IKK, blocks cancer-induced wasting, the alternative NF-B signaling pathway is not required. In addition, the downstream NF-B transcription factors do not regulate the transcriptional changes. These data are consistent with the growing body of literature showing that there are NF-B-independent substrates of IKK and IB that regulate physiological processes.

6

Cornwell EW, Mirbod A, Wu CL, Kandarian SC, Jackman RW