Apoptosis in nontumorous and neoplastic human pituitaries - Expression of the Bcl-2 family of proteins

Analyses of apoptosis and of the apoptosis regulatory proteins Bcl-2, Bar, Bcl-X, and Bad were done In 95 nontumorous and neoplastic pituitary tissues by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (T UNEL), immunohistochemistry, and Western blotting. The apoptotic index was relatively low in all groups but was at least fourfold higher in pituitary carcinomas compared with any other groups. Pituitaries from pregnant and po stpartum women had a fivefold higher apoptotic index compared with matched controls from nonpregnant females. Preoperative treatment of adenomas with octreotide or dopamine agonists did not change the apoptotic index signific antly. The lowest levels of Bcl-2, Bar, and Bcl-X expression were in pituit ary carcinomas as detected by immunostaining, An immortalized human pituita ry adenoma cell line, HP75, developed In our laboratory using a replication -defective recombinant human adenovirus with an early large T-antigen, had a much higher level of apoptosis than nontumorous and neoplastic pituitarie s. Treatment with transforming growth factor (TGF)-beta 1 and protein kinas e C (PKC) inhibitors increased apoptosis in this cell line. Analysis of the Bcl-2 family of proteins after treatment with TGF-beta 1 and PKC inhibitor s showed a 20% to 30% decrease in Bcl-X in the treated groups compared with controls. These results, which represent the first study of apoptosis in p ituitaries from pregnant and postpartum cases and in pituitary carcinomas, indicate that 1) the apoptotic rate is low in nontumorous and neoplastic pi tuitary tissues but is relatively higher in pituitary carcinomas, 2) there are alterations in the expression of the Bcl-2 family of proteins in pituit ary neoplasms with a decrease in Bcl-2 expression In pituitary carcinomas t hat may contribute to pituitary tumor pathogenesis and/or proliferation, an d 3) cultured pituitary tumor cells respond to TGF-beta 1 and PKC inhibitor s by undergoing apoptotic cell death.