Tamoxifen Exerts Anticancer Effects on Pituitary Adenoma Progression via Inducing Cell Apoptosis and Inhibiting Cell Migration

• Published in: International journal of molecular sciences 2022-02, Vol.23 (5), p.2664
• Main Authors: Lv, Tingting, Zhang, Zirui, Yu, Haoying, Ren, Shuyue, Wang, Jingrong, Li, Shang, Sun, Lan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenoma; Adenoma - genetics; AKT protein; Animals; Apoptosis; BAX protein; Bcl-2 protein; Cancer therapies; Cardiovascular diseases; Cell cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug dosages; Gene expression; genomics; Humans; Immune checkpoint; Kinases; Macrophages; Mice; Mice, Nude; migration; Nitric oxide; p53 Protein; Phenotypes; Phosphorylation; Pituitary; pituitary adenomas; Pituitary Neoplasms - pathology; Proteins; SHP-1 protein; Stat6 protein; Tamoxifen; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Tumor cell lines; tumor-associated macrophages; Tumors; Xenografts; Xenotransplantation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23052664

Although pituitary adenomas are histologically benign, they are often accompanied by multiple complications, such as cardiovascular disease and metabolic dysfunction. In the present study, we repositioned the Food and Drug Administration -approved immune regulator tamoxifen to target STAT6 based on the genomics analysis of PAs. Tamoxifen inhibited the proliferation of GH3 and AtT-20 cells with respective IC values of 9.15 and 7.52 μM and increased their apoptotic rates in a dose-dependent manner. At the molecular level, tamoxifen downregulated phosphorylated PI3K, phosphorylated AKT and the anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic proteins p53 and Bax in GH3 and AtT-20 cells. Furthermore, tamoxifen also inhibited the migration of both cell lines by reprogramming tumor-associated macrophages to the M1 phenotype through STAT6 inactivation and inhibition of the macrophage-specific immune checkpoint SHP1/SHP. Finally, administration of tamoxifen (20, 50, 100 mg·kg ·d , for 21 days) inhibited the growth of pituitary adenomas xenografts in nude mice in a dose-dependent manner. Taken together, tamoxifen is likely to be a promising combination therapy for pituitary adenomas and should be investigated further.