GAS2-Calpain2 axis contributes to the growth of leukemic cells
GAS2-Calpain2 axis contributes to the growth of leukemic cells
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GAS2-Calpain2轴有助于白血病细胞的生长
DOI：
10.1093/abbs/gmv080
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发表时间：
2015-10-01
影响因子：
3.7
通讯作者：
Zhao, Yun
中科院分区：
文献类型：
--
作者：
Sun, Lili;Zhou, Haixia;Zhao, Yun
生长抑制特异性2 （GAS2）调节细胞周期、凋亡和Calpain活性。GAS2-Calpain2轴是BCR-ABL（+）造血细胞和慢性髓系白血病细胞生长所必需的。然而，GAS2在急性白血病患者中的表达尚不清楚，GAS2- calpain2轴在这些白血病细胞中起什么作用尚不清楚。在本研究中，GAS2在16种白血病细胞系中的表达明显高于对照细胞。以THP-1细胞（来自急性髓性白血病患者，AML）和Jurkat细胞（来自急性淋巴性白血病患者，ALL）为模型，我们发现GAS2沉默导致Calpain活性升高，细胞生长下降，集落形成细胞（CFC）产生抑制；这些作用可以通过GAS2的重新表达来恢复。此外，GAS2沉默可阻止裸小鼠THP-1细胞的肿瘤形成。在THP-1和Jurkat细胞中，GAS2与Calpain2而不是Calpain1相互作用。GAS2的显性阴性形式（GAS2DN, GAS2 Delta 171-313）通过激活Calpain对白血病细胞具有类似的作用。重要的是，Calpain2沉默消除了GAS2靶向诱导的增殖抑制。我们还发现急性白血病患者临床分离株中GAS2表达异常，Calpain活性降低。综上所述，我们的研究结果证明了AML和ALL中GAS2的失调以及GAS2- calpain2轴对白血病细胞生长的需求，这将有助于了解血液系统恶性肿瘤的分子发病机制，并可能开发治疗这些致命疾病的新方法。
Growth arrest specific 2 (GAS2) modulates cell cycle, apoptosis, and Calpain activity. GAS2-Calpain2 axis is required for the growth of BCR-ABL(+) hematopoietic cells and chronic myeloid leukemia cells. However, the expression of GAS2 in acute leukemia patients remains unclear and what role GAS2-Calpain2 axis plays in these leukemic cells is not known yet. In this study, GAS2 was found to have significantly higher expression in 16 various leukemic cell lines than in control cells. Using THP-1 cells (from acute myeloid leukemia patient, AML) and Jurkat cells (from acute lymphoid leukemia patient, ALL) as models, we found that GAS2 silence led to elevated Calpain activity, decreased cellular growth, and inhibition of colony-forming cell (CFC) production; and these effects could be rescued by GAS2 re-expression. Moreover, GAS2 silence prevented tumor formation of THP-1 cells in nude mice. In both THP-1 and Jurkat cells, GAS2 interacted with Calpain2 rather than Calpain1. The dominant negative form of GAS2 (GAS2DN, GAS2 Delta 171-313) had similar effects on leukemic cells through the activation of Calpain. Importantly, Calpain2 silence abolished the proliferation inhibition induced by GAS2 targeting. We also found that GAS2 was aberrantly expressed and Calpain activity was decreased in clinical isolates from acute leukemia patients. Taken together, our results demonstrated the deregulation of GAS2 in both AML and ALL and the requirement of GAS2-Calpain2 axis for the growth of leukemic cells, which will help to understand the molecular pathogenesis of hematological malignancies and possibly to develop novel approaches to treat these deadly diseases.