Kulig E, Jin L, Qian X, Horvath E, Kovacs K, Stefaneanu L, Scheithauer B W, Lloyd R V
Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Am J Pathol. 1999 Mar;154(3):767-74. doi: 10.1016/S0002-9440(10)65323-0.
Analyses of apoptosis and of the apoptosis regulatory proteins Bcl-2, Bax, Bcl-X, and Bad were done in 95 nontumorous and neoplastic pituitary tissues by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL), 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 postpartum 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 significantly. The lowest levels of Bcl-2, Bax, and Bcl-X expression were in pituitary carcinomas as detected by immunostaining. An immortalized human pituitary 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 pituitaries. Treatment with transforming growth factor (TGF)-beta1 and protein kinase C (PKC) inhibitors increased apoptosis in this cell line. Analysis of the Bcl-2 family of proteins after treatment with TGF-beta1 and PKC inhibitors 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 pituitaries from pregnant and postpartum cases and in pituitary carcinomas, indicate that 1) the apoptotic rate is low in nontumorous and neoplastic pituitary tissues but is relatively higher in pituitary carcinomas, 2) there are alterations in the expression of the Bcl-2 family of proteins in pituitary neoplasms with a decrease in Bcl-2 expression in pituitary carcinomas that may contribute to pituitary tumor pathogenesis and/or proliferation, and 3) cultured pituitary tumor cells respond to TGF-beta1 and PKC inhibitors by undergoing apoptotic cell death.
通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）、免疫组织化学和蛋白质印迹法，对95份非肿瘤性和肿瘤性垂体组织进行了凋亡及凋亡调节蛋白Bcl-2、Bax、Bcl-X和Bad的分析。所有组的凋亡指数相对较低，但垂体癌的凋亡指数比其他任何组至少高四倍。与未怀孕女性的匹配对照相比，怀孕和产后女性的垂体凋亡指数高五倍。用奥曲肽或多巴胺激动剂对腺瘤进行术前治疗，并未显著改变凋亡指数。免疫染色检测发现，垂体癌中Bcl-2、Bax和Bcl-X的表达水平最低。我们实验室使用携带早期大T抗原的复制缺陷型重组人腺病毒构建的永生化人垂体腺瘤细胞系HP75，其凋亡水平比非肿瘤性和肿瘤性垂体高得多。用转化生长因子（TGF）-β1和蛋白激酶C（PKC）抑制剂处理可增加该细胞系的凋亡。用TGF-β1和PKC抑制剂处理后，对Bcl-2蛋白家族的分析显示，与对照组相比，处理组的Bcl-X减少了20%至30%。这些结果是对怀孕和产后垂体以及垂体癌凋亡的首次研究，表明：1）非肿瘤性和肿瘤性垂体组织的凋亡率较低，但垂体癌的凋亡率相对较高；2）垂体肿瘤中Bcl-2蛋白家族的表达存在改变，垂体癌中Bcl-2表达降低，这可能有助于垂体肿瘤的发病机制和/或增殖；3）培养的垂体肿瘤细胞对TGF-β1和PKC抑制剂有反应，通过凋亡细胞死亡。
