Aurora-A down-regulates IkappaBalpha via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival.
Aurora-A down-regulates IkappaBalpha via Akt activation and interacts with insulin-like growth factor-1 induced phosphatidylinositol 3-kinase pathway for cancer cell survival.
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Aurora-A 通过 Akt 激活下调 IkappaBalpha，并与胰岛素样生长因子 1 诱导的磷脂酰肌醇 3 激酶通路相互作用，从而促进癌细胞存活。
DOI：
10.1186/1476-4598-8-95
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发表时间：
2009-11-05
期刊：
影响因子：
37.3
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Yao JE;Yan M;Guan Z;Pan CB;Xia LP;Li CX;Wang LH;Long ZJ;Zhao Y;Li MW;Zheng FM;Xu J;Lin DJ;Liu Q
有丝分裂Aurora-A激酶在维持有丝分裂保真度方面发挥着至关重要的作用。作为一种真正的癌蛋白，Aurora-A的异常过表达会导致致癌转化。然而，Aurora-A增强癌细胞存活的机制仍有待阐明。本研究发现，Aurora-A过表达与舌癌临床分期及淋巴结转移密切相关。Aurora-A抑制VX-680抑制癌细胞增殖，诱导细胞凋亡，显著减少癌细胞迁移。我们进一步发现胰岛素样生长因子-1，PI3K生理激活剂，逆转vx -680降低的细胞存活和运动。相反，PI3K抑制剂wortmannin与VX-680联合在诱导凋亡和抑制迁移方面表现出协同作用。此外，Aurora-A抑制抑制了Akt的激活，并且vx -680诱导的细胞凋亡被Myr-Akt过表达所减弱，这表明Aurora-A和PI3K通路在Akt激活时相互作用。值得注意的是，我们发现Aurora-A的抑制降低了磷酸化的Akt，并增加了IkappaBα的表达。相反，Aurora-A过表达上调Akt活性，下调IkappaBα，这些变化伴随着核因子-κB的核易位及其靶基因Bcl-xL的表达增加。最后，Aurora-A过表达诱导的IkappaBα减少可通过化学或基因抑制Akt来消除。综上所述，我们的数据表明，Aurora-A通过激活Akt，刺激核因子-κB信号通路，促进癌细胞存活，并有望为癌症治疗提供一种新的针对Aurora-A和PI3K的联合化疗方案。
The mitotic Aurora-A kinase exerts crucial functions in maintaining mitotic fidelity. As a bona fide oncoprotein, Aurora-A aberrant overexpression leads to oncogenic transformation. Yet, the mechanisms by which Aurora-A enhances cancer cell survival remain to be elucidated. Here, we found that Aurora-A overexpression was closely correlated with clinic stage and lymph node metastasis in tongue carcinoma. Aurora-A inhibitory VX-680 suppressed proliferation, induced apoptosis and markedly reduced migration in cancer cells. We further showed that insulin-like growth factor-1, a PI3K physiological activator, reversed VX-680-decreased cell survival and motility. Conversely, wortmannin, a PI3K inhibitor, combined with VX-680 showed a synergistic effect on inducing apoptosis and suppressing migration. In addition, Aurora-A inhibition suppressed Akt activation, and VX-680-induced apoptosis was attenuated by Myr-Akt overexpression, revealing a cross-talk between Aurora-A and PI3K pathway interacting at Akt activation. Significantly, we showed that suppression of Aurora-A decreased phosphorylated Akt and was associated with increased IkappaBα expression. By contrast, Aurora-A overexpression upregulated Akt activity and downregulated IkappaBα, these changes were accompanied by nuclear translocation of nuclear factor-κB and increased expression of its target gene Bcl-xL. Lastly, Aurora-A overexpression induced IkappaBα reduction was abrogated by suppression of Akt either chemically or genetically. Taken together, our data established that Aurora-A, via activating Akt, stimulated nuclear factor-κB signaling pathway to promote cancer cell survival, and promised a novel combined chemotherapy targeting both Aurora-A and PI3K in cancer treatment.
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影响因子：
6.2
作者：
Massarelli, E;Liu, DD;Papadimitrakopoulou, VA
通讯作者：
Papadimitrakopoulou, VA
影响因子：
11.2
作者：
Briassouli, Paraskevi;Chan, Florence;Linardopoulos, Spiros
通讯作者：
Linardopoulos, Spiros
影响因子：
9.2
作者：
Taga M;Hirooka E;Ouchi T
通讯作者：
Ouchi T
影响因子：
50.3
作者：
Anand, S;Penrhyn-Lowe, S;Venkitaraman, AR
通讯作者：
Venkitaraman, AR
DOI：
10.1073/pnas.0706493104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Irelan, Jeffrey T.;Murphy, Thomas J.;Chanda, Sumit K.
通讯作者：
Chanda, Sumit K.