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キーワード:
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要旨:
One function of the glucocorticoid receptor (GR) in corticotroph cells
is to suppress the transcription of the gene encoding
proopiomelanocortin (POMC), the precursor of the stress hormone
adrenocorticotropin (ACTH)(1). Cushing disease is a neuroendocrine
condition caused by partially glucocorticoid-resistant corticotroph
adenomas that excessively secrete ACTH, which leads to
hypercortisolism(2-4). Mutations that impair GR function explain
glucocorticoid resistance only in sporadic cases(5,6). However, the
proper folding of GR depends on direct interactions with the chaperone
heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph
adenomas overexpress HSP90 compared to the normal pituitary. N- and
C-terminal HSP90 inhibitors act at different steps of the HSP90
catalytic cycle to regulate corticotroph cell proliferation and GR
transcriptional activity. C-terminal inhibitors cause the release of
mature GR from HSP90, which promotes its exit from the chaperone cycle
and potentiates its transcriptional activity in a corticotroph cell line
and in primary cultures of human corticotroph adenomas. In an allograft
mouse model, the C-terminal HSP90 inhibitor silibinin showed
anti-tumorigenic effects, partially reverted hormonal alterations, and
alleviated symptoms of Cushing disease. These results suggest that the
pathogenesis of Cushing disease caused by overexpression of heat shock
proteins and consequently misregulated GR sensitivity may be overcome
pharmacologically with an appropriate HSP90 inhibitor.
