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Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas

Nature Medicine volume 8, pages 1281–1287 (2002)Cite this article

Abstract

Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-γ was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-γ activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease

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Figure 1: Pituitary PPAR-γ expression is restricted to normal human corticotroph cells.
Figure 2: PPAR-γ is abundantly expressed in human ACTH-secreting pituitary tumors.
Figure 3: Functional PPAR-γ in pituitary corticotroph tumors.
Figure 4: TZDs inhibit corticotroph cell proliferation, ACTH synthesis and secretion, and induce apoptosis.
Figure 5: Rosiglitazone inhibits corticotroph pituitary tumor growth in vivo.
Figure 6: Rosiglitazone treatment retards growth of established pituitary corticotroph tumors and suppresses steroid hormone levels in vivo (n = 5).

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Acknowledgements

This study was supported by the Doris Factor Molecular Endocrinology Laboratory, the Annenberg Foundation and NIH grant CA75979.

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Authors and Affiliations

  1. Department of Medicine, Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California, USA

    Anthony P. Heaney, Manory Fernando & Shlomo Melmed

  2. Department of Pathology, Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California, USA

    William H. Yong

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  1. Anthony P. Heaney
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Correspondence to Anthony P. Heaney.

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Heaney, A., Fernando, M., Yong, W. et al. Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med 8, 1281–1287 (2002). https://doi.org/10.1038/nm784

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