Lower Tubulin Expression in Glioblastoma Stem Cells Attenuates Efficacy of Microtubule-Targeting Agents.,ACS Pharmacology & Translational Science

当前位置： X-MOL 学术 › ACS Pharmacol. Transl. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Lower Tubulin Expression in Glioblastoma Stem Cells Attenuates Efficacy of Microtubule-Targeting Agents.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-08-13 , DOI: 10.1021/acsptsci.9b00045
Ramzi H Abbassi ₁ , Ariadna Recasens ₁ , Dinesh C Indurthi ₁ , Terrance G Johns ₂ , Brett W Stringer ₃ , Bryan W Day ₃ , Lenka Munoz ₁

Affiliation

Sensitivity to microtubule-targeting agents (MTAs) varies among cancers and predicting the response of individual cancer patients to MTAs remains challenging. As microtubules possess vast molecular heterogeneity generated by tubulin isotypes and their post-translational modifications, we questioned whether this heterogeneity can impact MTA sensitivity. We investigated microtubule heterogeneity in 15 glioblastoma cell lines and measured sensitivity of orthogonal MTAs using a per-division growth rate inhibition method that corrects for the confounding effects of variable cell proliferation rates. We found that the tubulin profile is unique for each glioblastoma cell line and that the total α- and β-tubulin levels impact on MTA sensitivity. The baseline levels of α- and β-tubulin were up to 20% lower in cells that were not effectively killed by MTAs. We report that lower α/β-tubulin expression is associated with lack of cell differentiation and increased expression of stemness markers. The dedifferentiated stem-like cells with low α/β-tubulin levels survive MTAs treatment via reversible nonmutational dormancy. Our findings provide novel insights into the relationships between microtubules and MTAs and lay a foundation for better understanding of the sensitivity of cancer cells to MTAs.

中文翻译：

胶质母细胞瘤干细胞中较低的微管蛋白表达减弱了微管靶向剂的功效。

在癌症中，对微管靶向剂（MTA）的敏感性各不相同，并且预测个别癌症患者对MTA的反应仍然具有挑战性。由于微管具有由微管蛋白同种型及其翻译后修饰产生的巨大分子异质性，我们质疑这种异质性是否会影响MTA敏感性。我们调查了15个胶质母细胞瘤细胞系中的微管异质性，并使用逐格生长速率抑制方法校正了可变细胞增殖速率的混杂效应，从而测量了正交MTA的敏感性。我们发现微管蛋白谱对于每种胶质母细胞瘤细胞系都是独特的，并且总的α-和β-微管蛋白水平对MTA敏感性有影响。在未被MTA有效杀死的细胞中，α-和β-微管蛋白的基线水平降低了20％。我们报道，较低的α/β-微管蛋白表达与细胞分化不足和茎标记的表达增加有关。具有低α/β-微管蛋白水平的去分化干细胞样细胞通过可逆的非突变休眠存活于MTA处理中。我们的发现为微管与MTA之间的关系提供了新颖的见解，并为更好地理解癌细胞对MTA的敏感性奠定了基础。

更新日期：2019-08-13

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文