Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.
Mol Cells. 2013 Aug;36(2):177-84. doi: 10.1007/s10059-013-0061-6. Epub 2013 Jul 4.
It has been suggested that activation of receptor PTKs is important for leukemogenesis and leukemia cell response to targeted therapy in hematological malignancies including leukemia. PTKs induce activation of the PI3K/Akt/mTOR pathway, which can result in prevention of apoptosis. Here, we describe an important role of the TrkC-associated molecular network in the process of leukemogenesis. TrkC was found to be frequently overexpressed in human leukemia cells and leukemia subtypes. In U937 human leukemia cells, blockade of TrkC using small hairpin RNA (shRNA) specific to TrkC or K562a, a specific inhibitor of TrkC, resulted in a significant decrease in growth and survival of the cells, which was closely associated with reduced mTOR level and Akt activity. In addition, TrkC enhances the survival and proliferation of leukemia, which is correlated with activation of the PI3K/Akt pathway. Moreover, TrkC significantly inhibits apoptosis via induction of the expression of PLK-1 and Twist-1 through activation of AKT/mTor pathway; therefore, it plays a key role in leukemogenesis. These findings reveal an unexpected physiological role for TrkC in the pathogenesis of leukemia and have important implications for understanding various hematological malignancies.
有人认为，受体 PTKs 的激活对于包括白血病在内的血液恶性肿瘤的白血病发生和白血病细胞对靶向治疗的反应很重要。PTKs 诱导 PI3K/Akt/mTOR 途径的激活，从而导致细胞凋亡的预防。在这里，我们描述了 TrkC 相关分子网络在白血病发生过程中的重要作用。发现 TrkC 在人类白血病细胞和白血病亚型中经常过表达。在 U937 人类白血病细胞中，使用针对 TrkC 的小发夹 RNA (shRNA) 或 K562a（TrkC 的特异性抑制剂）阻断 TrkC，会导致细胞生长和存活显著减少，这与 mTOR 水平和 Akt 活性降低密切相关。此外，TrkC 通过激活 AKT/mTor 通路诱导 PLK-1 和 Twist-1 的表达，增强白血病的存活和增殖，从而激活 PI3K/Akt 通路。此外，TrkC 通过激活 AKT/mTor 通路诱导 PLK-1 和 Twist-1 的表达，显著抑制细胞凋亡；因此，它在白血病发生中起着关键作用。这些发现揭示了 TrkC 在白血病发病机制中的意外生理作用，对理解各种血液恶性肿瘤具有重要意义。
