EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway.
EPS8 regulates proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway.
复制标题
EPS8 通过 BCR-ABL/PI3K/AKT/mTOR 通路调节 BCR-ABL 阳性细胞的增殖、凋亡和化疗敏感性。
DOI：
10.3892/or.2017.6102
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发表时间：
2018-01
期刊：
影响因子：
4.2
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Huang R;Liu H;Chen Y;He Y;Kang Q;Tu S;He Y;Zhou X;Wang L;Yang J;Wu A;Li Y
虽然酪氨酸激酶抑制剂的引入大大提高了慢性髓性白血病（CML）患者的生存率，但耐药性仍然是一个问题。因此，基于机制的新治疗靶点值得探索。最近，表皮生长因子受体激酶底物8 （EPS8）已被确定为一种致癌基因，在广泛的实体肿瘤中发挥重要作用，据报道与急性白血病患者预后不良或化疗耐药有关。然而，其在CML中的作用尚不清楚。在本研究中，我们使用q-RT-PCR证明CML患者骨髓单核细胞中EPS8 mRNA的表达水平高于健康对照组。然后，为了确定EPS8对CML细胞生物学功能的影响，我们在人CML细胞系K562中下调EPS8的表达。EPS8沉默后，K562细胞增殖减少，凋亡增加，粘附和迁移受损。值得注意的是，EPS8的衰减增加了对伊马替尼敏感的K562细胞和对伊马替尼耐药的小鼠BCR-ABL+ 32D-p210BCR/ABL-T315I细胞的化学敏感性。在机制上，EPS8的下调下调了p-BCR/ABL及其下游AKT/mTOR信号通路。最后，敲低EPS8可减弱BALB/c裸鼠中K562细胞的增殖。这些数据表明EPS8通过BCR-ABL/PI3K/AKT/mTOR通路调控BCR-ABL阳性细胞的增殖、凋亡和化学敏感性。单独靶向EPS8或联合酪氨酸激酶抑制剂可能是一种有希望的替代治疗策略。
Although the introduction of tyrosine kinase inhibitors greatly improved the survival of patients with chronic myeloid leukemia (CML), drug resistance remains a problem. Thus, mechanism-based novel therapeutic targets warrant exploration. Recently, epidermal growth factor receptor kinase substrate 8 (EPS8), which has been identified as an oncogene and plays an important role in a broad spectrum of solid tumours, was reported to be related to poor prognosis or chemoresistance in acute leukemia patients. However, its role in CML remains unclear. In the present study, using q-RT-PCR, we demonstrated that CML patients expressed a higher level of EPS8 mRNA in bone marrow mononuclear cells than healthy controls. Then, to determine the effect of EPS8 on the biological functions of CML cells, EPS8 expression was knocked down in the human CML cell line K562. Reduced proliferation, increased apoptosis, impaired adhesion and migration were observed in K562 cells after EPS8 silencing. Notably, attenuation of EPS8 increased chemosensitivity both in imatinib-sensitive K562 cells and in the imatinib-resistant murine BCR-ABL+ 32D-p210BCR/ABL-T315I cells. Mechanistically, knockdown of EPS8 downregulated p-BCR/ABL and its downstream AKT/mTOR signalling pathway. Finally, knockdown of EPS8 attenuated K562 cell proliferation in BALB/c nude mice. These data indicated that EPS8 regulated the proliferation, apoptosis and chemosensitivity in BCR-ABL positive cells via the BCR-ABL/PI3K/AKT/mTOR pathway. Targeting EPS8 alone or combined with a tyrosine kinase inhibitor may be a promising alternative therapeutic strategy.
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影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
11.4
作者：
Hochhaus, A.;O'Brien, S. G.;Larson, R. A.
通讯作者：
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0.7
作者：
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Li, Yu-Hua
影响因子：
20.3
作者：
Kang, Huining;Wilson, Carla S.;Willman, Cheryl L.
通讯作者：
Willman, Cheryl L.
影响因子：
4.7
作者：
Wang, Huixin;Patel, Vyomesh;Yeudall, W. Andrew
通讯作者：
Yeudall, W. Andrew