Lineage-specific restraint of pituitary gonadotroph cell adenoma growth

• Published in: PloS one 2011-03, Vol.6 (3), p.e17924-e17924
• Main Authors: Chesnokova, Vera, Zonis, Svetlana, Zhou, Cuiqi, Ben-Shlomo, Anat, Wawrowsky, Kolja, Toledano, Yoel, Tong, Yunguang, Kovacs, Kalman, Scheithauer, Bernd, Melmed, Shlomo
• Format: Article
• Language: English
• Subjects: Adenoma; Animals; Benign; Biomarkers, Tumor - metabolism; Brain cancer; Breast cancer; Carcinoma; CCAAT-Enhancer-Binding Proteins - metabolism; Cell cycle; Cell growth; Cell Lineage; Cell Proliferation; Cellular Senescence; Clusterin; Clusterin - genetics; Clusterin - metabolism; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-dependent kinase inhibitor p21; Cytokines; Deoxyribonucleic acid; DNA; DNA Damage; Forkhead Box Protein L2; Forkhead Transcription Factors - metabolism; Gene expression; Genetic engineering; Gonadotrophs - metabolism; Gonadotrophs - pathology; Growth; Growth hormone; Growth hormones; Humans; Immune system; Insulin-like growth factors; Kinases; Lung cancer; Medicine; Metastasis; Mice; Mice, Transgenic; Models, Biological; Neoplasm Proteins - metabolism; p53 Protein; Phenotype; Physicians; Pituitary; Pituitary (anterior); Pituitary gland; Pituitary Gland - metabolism; Pituitary Gland - pathology; Pituitary Neoplasms - metabolism; Pituitary Neoplasms - pathology; Pituitary tumor-transforming proteins; Promoter Regions, Genetic - genetics; Prostate cancer; Proteins; Rodents; Securin; Senescence; Transfection; Transgenic animals; Transgenic mice; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0017924

Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p  =  0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth.