Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Acta Haematol. 2014;131(1):59-69. doi: 10.1159/000353164. Epub 2013 Sep 19.
BACKGROUND/AIMS: Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway preferentially occurs in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of this disease. In this study, we investigated the role of PI3K isoforms on proliferation of aggressive MCL cells.
The changes in cell viability, cell cycle distribution and apoptosis induction by the PI3K isoform-selective inhibitors were evaluated. The molecular basis underlying the effects of the specific inhibition of PI3K isoforms was investigated by Western blot analysis.
Our results demonstrated that a class IA PI3K isoform is most commonly involved in the constitutive activation of Akt in aggressive MCL. Treatment with a p110α isoform-specific inhibitor induced prominent cell cycle arrest followed by apoptosis through complete abolishment of phosphorylated (p)-Akt and its downstream targets. An inhibitor of isoform p110δ induced moderate cell cycle arrest with downregulation of p-Akt and p-S6K. A dual inhibitor of p110α and p110δ GDC-0941 caused more prominent cell growth inhibition compared to selective p110α or p110δ inhibitors. Inhibition of the class IB PI3K isoform p110γ did not cause cell cycle arrest or induce apoptosis in MCL cells.
These findings suggest that the therapeutic ablation of class IA PI3K may be a promising strategy for the treatment of refractory, aggressive MCL.
背景/目的：磷脂酰肌醇 3-激酶（PI3K）/Akt/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路的组成性激活优先发生在套细胞淋巴瘤（MCL）侵袭性 blastoid 变体中，并与该病的发病机制有关。在这项研究中，我们研究了 PI3K 同工型在侵袭性 MCL 细胞增殖中的作用。
评估了 PI3K 同工型选择性抑制剂对细胞活力、细胞周期分布和凋亡诱导的变化。通过 Western blot 分析研究了特定抑制 PI3K 同工型的作用的分子基础。
我们的结果表明，IA 类 PI3K 同工型最常涉及侵袭性 MCL 中 Akt 的组成性激活。用 p110α 同工型特异性抑制剂治疗可通过完全消除磷酸化（p）-Akt 及其下游靶标诱导明显的细胞周期停滞，随后凋亡。p110δ 同工型抑制剂诱导适度的细胞周期停滞，下调 p-Akt 和 p-S6K。p110α 和 p110δ 的双重抑制剂 GDC-0941 与选择性 p110α 或 p110δ 抑制剂相比，引起更显著的细胞生长抑制。PI3K 同工型 p110γ 的抑制不会引起 MCL 细胞的细胞周期停滞或诱导凋亡。
这些发现表明，IA 类 PI3K 的治疗性消融可能是治疗难治性侵袭性 MCL 的一种有前途的策略。
