Activin effects on neoplastic proliferation of human pituitary tumors

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 pit uicytes. We investigated the effect of activin on proliferation in 16 clini cally nonfunctioning pituitary adenomas in primary culture. Treatment for 2 4 h with activin (0-10 ng/mL) significantly inhibited cell proliferation in 5 tumors (P < 0.05), as determined by [H-3]thymidine incorporation. In 9 t umors, we studied regulation of the cyclin-dependent kinase inhibitor p21(W AF1/cip1) as a potential activin mediator. In tumors with activin-inhibited proliferation, p21(WAF1/cip1) gene expression was up-regulated after 4 h i n 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 fol listatin isoforms, and three tumors expressed only the less potent form. Tu mors 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 effec t in a subgroup of human pituitary tumors.