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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1009-1015
Copyright © 2000 by The Endocrine Society

Original Studies

Activin Effects on Neoplastic Proliferation of Human Pituitary Tumors1

Daniel C. Danila, Warrick J. Inder2, Xun Zhang, Joseph M. Alexander, Brooke Swearingen, E. Tessa Hedley-Whyte and Anne Klibanski

Neuroendocrine Unit, Departments of Neurosurgery (B.S.), and Neuropathology (E.T.H.W.), Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Bulfinch 457, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: aklibanski{at}partners.org

Factors underlying growth regulation in human pituitary tumors are largely unknown. Activin functions as an antiproliferative cytokine in a number of cell types and is endogenously expressed in normal and neoplastic human pituicytes. We investigated the effect of activin on proliferation in 16 clinically nonfunctioning pituitary adenomas in primary culture. Treatment for 24 h with activin (0–10 ng/mL) significantly inhibited cell proliferation in 5 tumors (P < 0.05), as determined by [3H]thymidine incorporation. In 9 tumors, we studied regulation of the cyclin-dependent kinase inhibitor p21WAF1/cip1 as a potential activin mediator. In tumors with activin-inhibited proliferation, p21WAF1/cip1 gene expression was up-regulated after 4 h in a dose-dependent manner (0–100 ng/mL).

We also investigated tumor expression of follistatin messenger ribonucleic acid, an activin-binding protein with two isoforms of different potencies. In contrast to normal pituitary tissue, only four tumors expressed both follistatin isoforms, and three tumors expressed only the less potent form. Tumors in which activin induced antiproliferative responses showed diminished or no follistatin messenger ribonucleic acid expression compared to normal pituitary. These data indicate that activin has an antiproliferative effect in a subgroup of human pituitary tumors.




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