PBK/TOPK mediates promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis
PBK/TOPK mediates promyelocyte proliferation via Nrf2-regulated cell cycle progression and apoptosis
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DOI：
10.3892/or.2015.4308
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发表时间：
2015-12-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Wanggang
中科院分区：
文献类型：
--
作者：
Liu, Yuhong;Liu, Hui;Zhang, Wanggang
急性髓性白血病（AML）是一种涉及造血干细胞的疾病，其特征在于造血细胞分化受阻和克隆性肿瘤增殖增加。AML与不良患者结局相关。PBK/TOPK是来源于PDZ结合激酶（PBK）/T淋巴因子激活的杀伤（T-LAK）细胞来源的蛋白激酶（TOPK）的蛋白激酶。以往的研究表明，PBK/TOPK在血液肿瘤中表达。本研究旨在探讨PBK/TOPK在早幼粒细胞增殖中的作用及其分子机制。PBK/TOPK敲低（KD）显著降低NB 4和HL-60早幼粒细胞中的细胞增殖和活力。PBK/TOPK KD导致G2/M期细胞阻滞，这归因于cdc 2和cyclin B表达的降低。此外，PBK/TOPK KD引起细胞凋亡，如通过线粒体凋亡途径的激活和TUNEL阳性细胞的增加所证明的。PBK/TOPK KD诱导细胞线粒体功能障碍和ROS生成，抑制线粒体功能障碍和ROS生成可抑制PBK/TOPK KD诱导的细胞周期阻滞和凋亡。此外，PBK/TOPK KD降低Nrf 2表达和ARE结合活性。过表达Nrf 2可抑制PBK/TOPK KD诱导的cdc 2和cyclin B表达下降及细胞周期阻滞，并阻断ROS产生和细胞凋亡。基于文献和我们的结果，证明Nrf 2可能是介导PBK/TOPK发挥的细胞增殖促进作用的关键调节因子。PBK/TOPK稳定Nrf 2，严格调节ROS水平，促进细胞周期进程并抑制凋亡，有助于早幼粒细胞的增殖。我们的研究结果为PBK/TOPK介导的早幼粒细胞增殖的分子机制提供了新的见解，并阐明了AML的发病机制。
Acute myeloid leukemia (AML) is a disorder involving hematopoietic stem cells, characterized by blockage of hematopoietic cell differentiation and an increase in clonal neoplastic proliferation. AML is associated with poor patient outcome. PBK/TOPK is a protein kinase derived from PDZ-binding kinase (PBK)/T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK). Previous studies have shown that PBK/TOPK is expressed in hematologic tumors. In the present study, we aimed to investigate the role of PBK/TOPK in promyelocyte proliferation and to clarify the molecular mechanism. PBK/TOPK knockdown (KD) significantly decreased cell proliferation and viability in the NB4 and HL-60 promyelocytes. PBK/TOPK KD resulted in G2/M cell cycle arrest that attributed to a decrease in cdc2 and cyclin B expression. In addition, PBK/TOPK KD caused apoptosis, as evidenced by activation of the mitochondrial apoptotic pathway and an increase in TUNEL-positive cells. PBK/TOPK KD induced mitochondrial dysfunction and ROS generation, and inhibition of mitochondrial dysfunction and ROS production suppressed PBK/TOPK KD-induced cell cycle arrest and apoptosis. Moreover, PBK/TOPK KD decreased Nrf2 expression and ARE-binding activity. Overexpression of Nrf2 inhibited the PBK/TOPK KD-induced decrease in cdc2 and cyclin B expression and cell cycle arrest, and blocked ROS production and apoptosis. Based on literature and our results, it was demonstrated that Nrf2 may be a crucial regulator that mediates PBK/TOPK-exerted promotion of cell proliferation. PBK/TOPK stabilizes Nrf2, strictly regulates the ROS level, promotes cell cycle progression and inhibits apoptosis, contributing to the proliferation of promyelocytes. Our results provide new insights into the molecular mechanism of PBK/TOPK-mediated promyelocyte proliferation and shed light on the pathogenesis of AML.