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).