TY - JOUR
T1 - The balance of PI3K and ERK signaling is dysregulated in prolactinoma and modulated by dopamine
AU - Roof, Allyson K.
AU - Jirawatnotai, Siwanon
AU - Trudeau, Tammy
AU - Kuzyk, Crystal
AU - Wierman, Margaret E.
AU - Kiyokawa, Hiroaki
AU - Gutierrez-Hartmann, Arthur
N1 - Funding Information:
Financial Support: This work was supported by National Institutes of Health Grant R01 DK46868 (to A.G.-H.). S.J. is supported by Thailand Research Fund RSA5880038, the Siriraj Research Fund, the Foundation for Cancer Care, and the Cha-lermphrakiat Grant, Faculty of Medicine Siriraj Hospital, Mahidol University.
Funding Information:
We acknowledge and thank Dr. Paul Albert (University of Ottawa) for his contribution of D2R-expressing GH4C1 clones, Mei Xu (University of Colorado Anschutz Medical Campus) for preparation of human sample lysates, and Dr. Katja Kiseljak-Vassiliades (University of Colorado Anschutz Medical Campus) for providing de-identified patient information. We also thank the Functional Genomics Facility (University of Colorado Anschutz Medical Campus), which is supported by Cancer Center Support Grant P30CA046934.
Funding Information:
This work was supported by National Institutes of Health Grant R01 DK46868 (to A.G.-H.). S.J. is supported by Thailand Research Fund RSA5880038, the Siriraj Research Fund, the Foundation for Cancer Care, and the Cha-lermphrakiat Grant, Faculty of Medicine Siriraj Hospital, Mahidol University.
Publisher Copyright:
Copyright © 2018 Endocrine Society
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Prolactin-secreting adenomas, or prolactinomas, cause hypogonadism, osteoporosis, and infertility. Although dopamine agonists (DAs) are used clinically to treat prolactinoma and reduce prolactin secretion via cAMP inhibition, the precise mechanism by which DAs inhibit lactotrope proliferation has not been defined. In this study, we report that phosphatidylinositol 3-kinase (PI3K) signals through AKT and mTOR to drive proliferation of pituitary somatolactotrope GH4T2 cells. We demonstrate that the DA cabergoline reduces activity of the mTOR effector s6K and diminishes GH4T2 cell proliferation primarily via activation of the long isoform of the dopamine D2 receptor (D2R). Dysfunctional D2R-mediated signaling and/or downregulated D2R expression is thought be the primary mechanism of DA resistance, which is observed in 10% to 20% of prolactinoma tumors. Dopamine-mediated D2R activation results in ERK stimulation and PI3K inhibition, suggesting that these two pathways act in an inverse manner to maintain lactotrope homeostasis. In this study, we found that ERK1/2-mediated prolactin transcription is inhibited by PI3K/CDK4-driven cell cycle progression, emphasizing that the ERK and PI3K signaling pathways oppose one another in lactotrope cells under homeostatic conditions. Lastly, we show that both ERK1/2 and AKT are activated in prolactinoma, demonstrating that the balance of ERK and AKT is dysregulated in human prolactinoma. Our findings reveal a potential use for dual pharmacological inhibitors of ERK and AKT as an alternative treatment strategy for DA-resistant prolactinomas.
AB - Prolactin-secreting adenomas, or prolactinomas, cause hypogonadism, osteoporosis, and infertility. Although dopamine agonists (DAs) are used clinically to treat prolactinoma and reduce prolactin secretion via cAMP inhibition, the precise mechanism by which DAs inhibit lactotrope proliferation has not been defined. In this study, we report that phosphatidylinositol 3-kinase (PI3K) signals through AKT and mTOR to drive proliferation of pituitary somatolactotrope GH4T2 cells. We demonstrate that the DA cabergoline reduces activity of the mTOR effector s6K and diminishes GH4T2 cell proliferation primarily via activation of the long isoform of the dopamine D2 receptor (D2R). Dysfunctional D2R-mediated signaling and/or downregulated D2R expression is thought be the primary mechanism of DA resistance, which is observed in 10% to 20% of prolactinoma tumors. Dopamine-mediated D2R activation results in ERK stimulation and PI3K inhibition, suggesting that these two pathways act in an inverse manner to maintain lactotrope homeostasis. In this study, we found that ERK1/2-mediated prolactin transcription is inhibited by PI3K/CDK4-driven cell cycle progression, emphasizing that the ERK and PI3K signaling pathways oppose one another in lactotrope cells under homeostatic conditions. Lastly, we show that both ERK1/2 and AKT are activated in prolactinoma, demonstrating that the balance of ERK and AKT is dysregulated in human prolactinoma. Our findings reveal a potential use for dual pharmacological inhibitors of ERK and AKT as an alternative treatment strategy for DA-resistant prolactinomas.
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U2 - 10.1210/en.2017-03135
DO - 10.1210/en.2017-03135
M3 - Article
C2 - 29726995
AN - SCOPUS:85054722992
VL - 159
SP - 2421
EP - 2434
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 6
ER -