双重PI3K/mToR抑制剂奥米帕利司/GSK2126458抑制神经皮肤黑素沉着症致癌转化细胞的克隆生长。
The Dual PI3K/mToR Inhibitor Omipalisib/GSK2126458 Inhibits Clonogenic Growth in Oncogenically-transformed Cells from Neurocutaneous Melanocytosis.
作者信息
Basu Dipanjan, Salgado Cláudia M, Bauer Bruce, Khakoo Yasmin, Patel Janki R, Hoehl Ryan M, Bertolini Dominique M, Zabec Joie, Brzozowski Morgan R, Reyes-Múgica Miguel
机构信息
Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA, U.S.A
Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA, U.S.A.
出版信息
Cancer Genomics Proteomics. 2018 Jul-Aug;15(4):239-248. doi: 10.21873/cgp.20082.
Abstract
BACKGROUND
Omipalisib has been found to affect the viability of cancer cells. However, its effect on clonogenicity - a feature of cancer stem cells, is not clear. Cells isolated from neurocutaneous melanocytosis (NCM) patients' lesions grow clonogenically. The aim of this study was to investigate the effect of omipalisib treatment on clonogenic growth of NCM cells in vitro.
MATERIALS AND METHODS
Clonogenic growth efficiency was evaluated by colony formation assays with or without specific growth factors. Activation of MEK and Akt was determined by immunoblots. Colony formation and cell viability were assessed upon pharmacological inhibition of MEK, Akt and mToR.
RESULTS
Clonogenicity appeared to depend on bFGF and IGF1signaling through ERK and Akt. Omipalisib treatment prevented colony formation and induced autophagic cell death.
CONCLUSION
Signaling through Akt is important for survival of clonogenic cells in NCM, and omipalisib treatment as a monotherapy or in combination with MEK162 could be an effective therapeutic strategy to inhibit clonogenic growth.
摘要
背景
已发现奥米帕利西布会影响癌细胞的活力。然而，其对克隆形成能力（癌症干细胞的一个特征）的影响尚不清楚。从神经皮肤黑素沉着症（NCM）患者病变部位分离出的细胞具有克隆生长能力。本研究的目的是调查奥米帕利西布处理对体外培养的NCM细胞克隆生长的影响。
材料与方法
通过有无特定生长因子的集落形成试验评估克隆生长效率。通过免疫印迹法测定MEK和Akt的激活情况。在对MEK、Akt和mToR进行药理抑制后评估集落形成和细胞活力。
结果
克隆形成能力似乎依赖于通过ERK和Akt的bFGF和IGF1信号传导。奥米帕利西布处理可阻止集落形成并诱导自噬性细胞死亡。
结论
通过Akt的信号传导对NCM中克隆形成细胞的存活很重要，奥米帕利西布单药治疗或与MEK162联合使用可能是抑制克隆生长的有效治疗策略。
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