Endocrine Abstracts

Heat shock protein 90 (HSP90) plays a pivotal role in maturation and stabilization of proteins in conditions of stress. Many HSP90 client proteins are involved in oncogenic signaling and cancer progression, therefore HSP90 inhibitors have a potential as pharmaceutical agents. We reported a strong HSP90 overexpression in corticotroph adenomas and the treatment with C-terminal HSP90 inhibitors has potent anti-tumorigenic and anti-secretory effects in these tumors in vitro and in vivo. In the present study, we extended this investigation to the potential role of HSP90 in the pathogenesis of GH-secreting pituitary adenomas. We observed intense HSP90 immunoreactivity in 8 out of 25 GH-secreting pituitary tumors. To study the therapeutic potential of HSP90 inhibition in these tumors, we treated the GH-secreting tumor cell line GH3 with C- and N-terminal HSP90 inhibitors and measured luciferase activity under the control of the rat GH promoter. The C-terminal HSP90 inhibitors KU174 and novobiocin dose dependently decreased GH promoter activity and KU174 was more effective than novobiocin with maximal luciferase inhibition at 4 μM for KU174 (52%, P<0.05) and at 100 nM for novobiocin (33%, P<0.05) compared to control. In contrast, the treatment with the N-terminal inhibitor 17-AAG did not suppress GH promoter activity. KU174 significantly decreased GH levels, with maximal effect at 4 μM (85% secretion inhibition compared to controls). These results show a putative role for HSP90 in the tumorigenesis of some GH-secreting pituitary tumors and a potential for HSP90 C-terminal inhibitors for the management of excess GH secretion. Further experiments are needed to clarify the role of HSP90 in GH-secreting tumors and the mechanisms driving the inhibitory action of C-terminal HSP90 inhibitors on GH production and secretion.