Dependence on PI3K/Akt signaling for malignant rhabdoid tumor cell survival.
Dependence on PI3K/Akt signaling for malignant rhabdoid tumor cell survival.
复制标题
DOI：
10.1007/s00280-008-0796-5
复制
发表时间：
2009-04
影响因子：
3
通讯作者：
Wright, Cynthia
中科院分区：
文献类型：
--
作者：
Foster, Kristen;Wang, Yong;Zhou, Daohong;Wright, Cynthia
恶性横纹肌样肿瘤（MRT），虽然罕见，是最具侵略性的儿童恶性肿瘤之一。INI1是一种肿瘤抑制基因，也是SWI/SNF染色质重塑复合体的成员，INI1的缺失是这些肿瘤的复发性遗传特征，也是重要的诊断标志。我们之前已经证明了丝氨酸/苏氨酸激酶Akt和INI1以及其他SWI/SNF亚基之间的一种新的相互作用。这一点，再加上文献中的实验表明PI3K/Akt通路在MRT细胞中失调，使我们研究了该通路在该肿瘤类型中的激活和重要性。在这项研究中，我们使用MTT法来评估MRT细胞系对PI3K抑制的敏感性。Western blot分析和Raf pull - down实验检测PI3K/Akt失调的潜在机制。PI3K/Akt通路的抑制导致四种MRT细胞系的存活显著降低，其中三种细胞系表现出组成性的Akt活性。其中两个组成型活性Akt细胞系大量表达IGF-1R，而IGF-1R抑制剂NVP-AEW541降低了其中一个细胞的Akt磷酸化。第三个组成活性Akt细胞系表达突变型IGF-1R。我们的数据表明，PI3K/Akt通路是维持MRT细胞存活和生长的关键手段。因此，细胞采用各种机制来刺激这一途径，生长因子受体失调似乎是一种常见的方法。抑制PI3K通路或干扰IGF自分泌回路的药物可能在治疗MRT方面具有重要价值，MRT对传统化疗方法具有很大的耐药性。
Malignant rhabdoid tumors (MRT), although rare, are one of the most aggressive pediatric malignancies. Loss of INI1, a tumor suppressor gene and member of the SWI/SNF chromatin remodeling complex, is a recurrent genetic characteristic of these tumors and an important diagnostic marker. We have previously demonstrated a novel interaction between the serine/threonine kinase Akt and INI1, as well as other SWI/SNF subunits. This, coupled with experiments in the literature suggesting that the PI3K/Akt pathway is dysregulated in MRT cells, caused us to investigate the activation and importance of this pathway in this tumor type. In this study, we used MTT assays to evaluate the sensitivity of MRT cell lines to PI3K inhibition. Western blot analysis and Raf pulldown assays were used to examine potential mechanisms of PI3K/Akt dysregulation. Inhibition of the PI3K/Akt pathway caused a significant reduction in the survival of the four MRT cell lines tested, and three cell lines demonstrated constitutively active Akt. Two of these constitutively active Akt cell lines abundantly expressed IGF-1R and an inhibitor of IGF-1R, NVP-AEW541, reduced Akt phosphorylation in one of them. The third constitutively active Akt cell line appeared to express a mutant IGF-1R. Our data suggests that the PI3K/Akt pathway is a crucial means of maintaining the survival and growth of MRT cells. The cells therefore employ various mechanisms to stimulate this pathway, and growth factor receptor dysregulation appears to be a common method. Drugs that inhibit the PI3K pathway or interfere with IGF autocrine loops may be of great value in treating MRT, which is largely resistant to conventional chemotherapeutic approaches.
登录
查看更多内容
影响因子：
11.2
作者：
Banine, F;Bartlett, C;Sherman, LS
通讯作者：
Sherman, LS
影响因子：
8
作者：
Doan, DN;Veal, TM;Imbalzano, AN
通讯作者：
Imbalzano, AN
影响因子：
5.6
作者：
Burger, PC;Yu, IT;Perlman, EJ
通讯作者：
Perlman, EJ
影响因子：
64.8
作者：
Fryer, CJ;Archer, TK
通讯作者：
Archer, TK
影响因子：
4.8
作者：
Graff, JR;Konicek, BW;Neubauer, BL
通讯作者：
Neubauer, BL