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  3. Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06 Podcast
  4. Investigations on the role of Hsp90 in the pathogenic glucocorticoid resistance of corticotroph pituitary adenomas
The main function of glucocorticoids in corticotroph cells is to
suppress proopiomelanocortin, the precursor of the stress hormone
adrenocorticotropin (ACTH). Cushing’s disease is a rare but severe
neuroendocrine condition caused by partially glucocorticoid
resistant corticotroph adenomas, which consequently secrete
excessive amounts of ACTH in an uncontrolled fashion. The patients
suffer from chronic hypercortisolism due to excessive stimulation
of the adrenal glands by ACTH to produce glucocorticoids. Impairing
mutations of the glucocorticoid receptor (GR) only sporadically
explain the reduced glucocorticoid sensitivity in the adenomas –
the molecular mechanism behind the partial resistance is poorly
understood. The function of GR depends on direct interactions with
the molecular chaperone Hsp90. Both the reduction and
overexpression of Hsp90 impedes GR activity in different
experimental settings. Therefore, the expression of the inducible
Hsp90α isoform was determined in biopsy specimens of corticotroph
pituitary adenomas from patients with Cushing’s disease. Its strong
overexpression compared to normal human pituitary cells paved the
way to study its role in the function of corticotroph adenomas
using small molecules which target Hsp90. The three distinct Hsp90
inhibitors 17–AAG, Novobiocin and Silibinin showed
antiproliferative effects in AtT–20 cells through the degradation
of the oncogenic client kinase Cdc2, a hallmark of pharmacologic
inhibition of Hsp90. Surprisingly, only the N–terminal Hsp90
inhibitor 17–AAG caused the degradation of GR, as was reported also
for other Geldanamycin–based Hsp90 inhibitors. Neither Silibinin
nor the C–terminal Hsp90 inhibitor Novobiocin affected GR protein
levels. These converging effects led to the assumption that both
compounds bind to the same domain in Hsp90. It was shown here that
Novobiocin displaces Silibinin from the C–terminal domain of Hsp90,
and that these compounds dissociate mature GR from Hsp90 at the
biochemical level. As a result, increased levels of mature receptor
were present in the cell able to bind glucocorticoids with high
affinity. This novel molecular mechanism proved to potentiate GR
transcriptional activity in AtT–20 cells. The potentiation in GR
activity also led to enhanced suppression of ACTH elicited by low
concentrations of Dexamethasone in AtT–20 cells and in primary
cultures of human corticotroph adenomas from patients with
Cushing’s disease. In contrast, Silibinin did not show effects on
rat normal pituitary cells. Finally, Silibinin reduced tumor
growth, partially reverted hormonal alterations, and alleviated
symptoms in a mouse allograft model for Cushing’s disease. These
results suggest that the regulation of GR sensitivity by
overexpressed Hsp90 may represent a pharmacologically reversible
mechanism in the pathogenesis of this disease. Together, a proof of
principle is provided that the clinically safe Hsp90 inhibitor
Silibinin potentially restores glucocorticoid sensitivity in
corticotroph adenomas in vitro and in vivo, and that it might be
used to treat Cushing’s patients in the future.

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„Investigations on the role of Hsp90 in the pathogenic glucocorticoid resistance of corticotroph pituitary adenomas“

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