Enhanced HSP90-STAT3 interaction causes persistent STAT3 activation and muscle atrophy in patients and mice with cancer cachexia.
We first evaluated the expression level of HSP90, atrophy markers, and activation of STAT3 in muscle from cancer cachexia patients. As shown in Figure 1, there is a significantly increased expression of muscle atrophy markers, including myostatin, E3 ligases such as Atrogin-1 and MuRF1 in skeletal muscle of cancer cachexia patients; also, we detected the persistent activation of STAT3 accompanied by significantly increased expression of HSP90 in cachectic skeletal muscle (Figure 1a,b); by measuring the HSP90-STAT3 interaction using the immunoprecipitation, we observed a dramatic increase in the HSP90-STAT3 interaction in patient muscle with cancer cachexia (Figure 1c), indicating that HSP90 might be involved in the regulation of STAT3 activation during the pathological development of cancer cachexia.
To validate these findings, inoculated Balb/C mice with a mouse colon adenocarcinoma cell line C26 were used to establish an experimental cachexia mouse model; these mice showed typical cachectic symptoms, including progressive weight loss, dull and matted fur, and mental weakness, which was consistent with the previous reports (Tanaka et al., 1990). There was approximately 15-20% overall weight loss and obvious lean body mass weight loss in C26 tumor-bearing mice compared with that in non-tumor-bearing mice within 15 days after tumor inoculation (Figure S1a). Persistent STAT3 activation, as well as the enhanced expression of HSP90 and atrophy related molecular markers including myostatin, Atrogin-1, and MuRF1, were also detected in cachectic muscle from C26-bearing mice (Figure 1d,e), the increase of the HSP90-STAT3 interaction was also confirmed in the cachectic muscle of C26 tumor-bearing mice (Figure 1f).