Antiproliferative effects of metformin in cellular models of pheochromocytoma
| Autor: | Rafael Abe da Rocha Miranda, Lisa E.L. Romano, Cinthia Gabriel Meireles, Eliete Neves Silva Guerra, Marcela Martins de Paula Oliveira, Luiz Alberto Simeoni, Caroline Lourenço de Lima, Francisco de Assis Rocha Neves, Teisha Yo-Stella Brashaw, J. Paul Chapple, Adriana Lofrano-Porto |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system diseases
Cellular respiration Cell Survival Adrenal Gland Neoplasms Antineoplastic Agents Pheochromocytoma Mitochondrion Biochemistry Models Biological PC12 Cells Phosphatidylinositol 3-Kinases Endocrinology Cell Line Tumor medicine Animals Viability assay Phosphorylation Molecular Biology PI3K/AKT/mTOR pathway Cell Proliferation Membrane Potential Mitochondrial Chemistry Cell growth TOR Serine-Threonine Kinases Adenylate Kinase AMPK Metformin Rats Gene Expression Regulation Neoplastic HIF1A Von Hippel-Lindau Tumor Suppressor Protein Mutation Cancer research Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | Molecular and cellular endocrinology. 539 |
| ISSN: | 1872-8057 |
| Popis: | Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from adrenal medulla chromaffin cells. Malignancy and recurrence are rare but demand effective treatment. Metformin exerts antiproliferative effects in several cancer cell lines. We thus evaluated the effects of metformin on cell viability and proliferation, cellular respiration and AMPK-AKT-mTOR-HIFA proliferation pathway on a rat PCC cell line (PC12-Adh). We then addressed metformin's effects on the AMPK-AKT-mTOR-HIFA pathway on two human primary cultures: one from a VHL-mutant PCC and other from a sporadic PCC. Metformin (20 mM) inhibited PC12-Adh cell proliferation, and decreased oxygen consumption, ATP production and proton leak, in addition to loss of mitochondrial membrane potential. Further, metformin induced AMPK phosphorylation and impaired AMPK-PI3k-AKT-mTOR pathway activation. The mTOR pathway was also inhibited in human VHL-related PCC cells, however, in an AMPK-independent manner. Metformin-induced decrease of HIF1A levels was likely mediated by proteasomal degradation. Altogether our results suggest that metformin impairs PCC cellular proliferation. |
| Databáze: | OpenAIRE |
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