PI3K inhibition by BKM120 results in anti-proliferative effects on corticotroph tumor cells

Autor(es)

Oliveira, H. A. ^[1] ; Bueno, A. C. ^[2] ; Pugliesi, R. S. ^[1] ; da Silva Junior, R. M. P. ^[1] ; de Castro, M. ^[1] ; Martins, C. S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Mol Biol Lab, Endocrinol Div, Av Bandeirantes 3900, Bloco G, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Dept Pediat, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Endocrinological Investigation; JAN 2022.
• Citações Web of Science: 0

Resumo

Purpose Cushing's disease is associated with significant morbidity; thus, additional tumor-directed drugs with the potential to exert antineoplastic effects on corticotroph adenoma cells are desired. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway, which plays regulatory role in cell survival and proliferation, is activated in pituitary adenomas. The present study evaluated the effects of BKM120 (Buparlisib), an oral PI3K inhibitor, on cell viability, apoptosis, cell cycle phase distribution, and ACTH production in mouse corticotroph tumor cells. Methods AtT-20/D16v-F2 mouse pituitary corticotroph tumor cells were treated with increasing concentrations of BKM120 or vehicle. Cell viability was measured using an MTS-based assay. Apoptosis was evaluated by Annexin V staining. Cell cycle analysis was performed by propidium iodide DNA staining and flow cytometry. Gene expression of cell cycle regulators (Cdkn1b, Ccnd1, Ccne1, Cdk2, Cdk4, Myc, and Rb1) was assessed by qPCR. Protein expression of p27, total and phosphorylated Akt was assessed by Western blot. ACTH levels were measured in the culture supernatants by chemiluminescent immunometric assay. Results Treatment with BKM120 decreased AtT-20/D16v-F2 cell viability, induced a G0/G1 cell cycle arrest, reduced the phosphorylation of Akt at Serine 473, and increased p27 expression. Furthermore, BKM120 treatment diminished ACTH levels in the cell culture supernatants. Conclusion In vitro inhibition of PI3K/AKT pathway by BKM120 resulted in anti-proliferative effects on corticotroph tumor cells, decreasing cell viability and ACTH production. These encouraging findings shape the path for further experiments with the inhibition of PI3K/AKT pathway in Cushing's disease. (AU)

• Processo FAPESP: 14/03989-6 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica (NGS - Next-Generation Sequencing)
• Beneficiário: Margaret de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Temático