文章：

PI3Kδ和PI3Kγ亚型在多发性骨髓瘤微环境中调控促肿瘤信号方面具有不同功能

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment

原文发布日期：2017-03-10

DOI: 10.1038/bcj.2017.16

类型: Original Article

开放获取: 是

英文摘要：

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM.

摘要翻译： 

磷酸肌醇3-激酶与蛋白激酶B（PI3K-AKT）信号通路在多发性骨髓瘤中呈现上调表达。本研究联合运用短发夹RNA慢病毒介导的基因敲低与异构体特异性药物抑制手段，探讨了PI3K p110γ亚基在调控骨髓瘤增殖及骨髓微环境诱导的肿瘤相互作用中的功能，并与PI3K p110δ亚基抑制及PI3Kδ/γ双重抑制方案进行对比。研究发现骨髓瘤细胞粘附与迁移是PI3Kγ特异性功能，PI3Kδ抑制在相关实验中未显现影响。当使用可在体内达到浓度的双重PI3Kδ/γ抑制剂杜韦利布时，我们观察到经骨髓基质细胞与白介素-6激活的肿瘤细胞其S473位点AKT磷酸化水平降低。更重要的是，在骨髓基质细胞与肿瘤共培养激活体系中，仅双重PI3Kδ/γ抑制能诱导骨髓瘤细胞凋亡。通过慢病毒shRNA单独靶向PI3Kδ或PI3Kγ以及联合靶向两者，均能延长移植骨髓瘤细胞的NSG小鼠生存期。此外，杜韦利布治疗在体内实验中降低了骨髓瘤负荷。本研究证实PI3Kδ与PI3Kγ异构体在骨髓瘤中具有独特功能，联合抑制双异构体具有抗骨髓瘤活性，为开展PI3Kδ/γ双重抑制的临床试验提供了科学依据。

原文链接：

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment