安普克
二甲双胍
PI3K/AKT/mTOR通路
蛋白激酶B
细胞生物学
细胞生长
癌症研究
化学
内分泌学
内科学
磷酸化
生物
信号转导
蛋白激酶A
医学
胰岛素
生物化学
作者
Cinthia Gabriel Meireles,Caroline Lourenço de Lima,Marcela Martins de Paula Oliveira,Rafael Abe da Rocha Miranda,Lisa E.L. Romano,Teisha Yo-Stella Brashaw,Eliete Neves Silva Guerra,Francisco de Assis Rocha Neves,J. Paul Chapple,Luiz Alberto Simeoni,Adriana Lofrano‐Porto
标识
DOI:10.1016/j.mce.2021.111484
摘要
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.
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