STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion
Cuiqi Zhou, … , Kolja Wawrowsky, Shlomo Melmed
Cuiqi Zhou, … , Kolja Wawrowsky, Shlomo Melmed
Published March 16, 2015
Citation Information: J Clin Invest. 2015;125(4):1692-1702. https://doi.org/10.1172/JCI78173.
View: Text | PDF
Research Article Endocrinology

STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion

Abstract

Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph adenoma tissue array. Promoter and expression analysis in a GH-secreting rat cell line (GH3) revealed that STAT3 specifically binds the Gh promoter and induces transcription. Stable expression of STAT3 in GH3 cells induced expression of endogenous GH, and expression of a constitutively active STAT3 further enhanced GH production. Conversely, expression of dominant-negative STAT3 abrogated GH expression. In primary human somatotroph adenoma-derived cell cultures, STAT3 suppression with the specific inhibitor S3I-201 attenuated GH transcription and reduced GH secretion in the majority of derivative cultures. In addition, S3I-201 attenuated somatotroph tumor growth and GH secretion in a rat xenograft model. GH induced STAT3 phosphorylation and nuclear translocation, indicating a positive feedback loop between STAT3 and GH in somatotroph tumor cells. Together, these results indicate that adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression, and suggest STAT3 as a potential therapeutic target for pituitary somatotroph adenomas.

Authors

Cuiqi Zhou, Yonghui Jiao, Renzhi Wang, Song-Guang Ren, Kolja Wawrowsky, Shlomo Melmed

×

Figure 6

STAT3 inhibitor S3I-201 constrains somatotroph cell growth in vitro and somatotroph xenograft growth in vivo.

Options: View larger image (or click on image) Download as PowerPoint
STAT3 inhibitor S3I-201 constrains somatotroph cell growth in vitro and ...
(A) S3I-201 decreases GH3 cell growth in vitro. GH3 cells were treated with increasing amounts of S3I-201. Cell growth was measured by premixed WST-1 cell proliferation assay or BrdU incorporation. Experiments were repeated 2 or 3 times, and representative experiments are shown. (B) S3I-201 attenuated GH3 somatotroph xenograft growth in vivo. Thirty Wistar Furth rats were subcutaneously injected with GH3 cells. After 1 week, S3I-201 or vehicle (n = 15 per group) was injected intravenously at 5 mg/kg every 2 or 3 days for 2 weeks. Tumor size of the 30 rats was assessed twice a week, and tumor volume was calculated. Two weeks after treatment, animals were euthanized, and all 30 tumors were excised and weighed. (C) S3I-201 decreased xenograft Gh mRNA expression. Xenograft Stat3 and Gh expression was assessed by real-time PCR, using Gapdh as a control. (D) S3I-201 decreased xenograft GH secretion. Blood samples were collected 1 day before treatment and on the day of euthanization. Serum GH and IGF1 levels were measured by RIA or ELISA, and fold change was calculated as serum level after treatment/serum level pretreatment. Results are presented as mean ± SEM, n = 15. Student’s t test, *P < 0.01, **P < 0.05.