N-Myc down regulation induced differentiation, early cell cycle exit, and apoptosis in human malignant neuroblastoma cells having wild type or mutant p53.
N-Myc down regulation induced differentiation, early cell cycle exit, and apoptosis in human malignant neuroblastoma cells having wild type or mutant p53.
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DOI：
10.1016/j.bcp.2009.06.009
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发表时间：
2009-11-01
影响因子：
5.8
通讯作者：
Ray, Swapan K.
中科院分区：
文献类型：
--
作者：
Janardhanan, Rajiv;Banik, Naren L.;Ray, Swapan K.
神经母细胞瘤主要发生在儿童中，是交感神经系统的侵袭性转移性肿瘤。先前的治疗方案未能针对 N-Myc 通路的多个成分，导致预后不良。本研究调查了 N-(4-羟苯基) 视黄酰胺（4-HPR，0.5 μM）和染料木黄酮（GST，25 μM）组合控制具有不同分子属性的人神经母细胞瘤细胞（SH-SY5Y 和 SK-N-BE2）生长的功效。 4-HPR 和 GST 组合下调 N-Myc、Notch-1 和 Id2，诱导神经元分化。向神经元表型的转变伴随着 e-钙粘蛋白表达的增加。神经元分化的诱导与 hTERT、PCNA、生存素和纤连蛋白表达的降低相关。这是首次报道 4-HPR 和 GST 组合介导神经母细胞瘤细胞中多种肿瘤抑制因子（p53、p21、Rb 和 PTEN）的重新激活，导致早期细胞周期退出（由于 G1/S 期停滞）。肿瘤抑制因子的重新激活抑制了神经母细胞瘤中 N-Myc 驱动的生长因子介导的血管生成和侵袭途径（VEGF、b-FGF、MMP-2 和 MMP-9）。血管生成因子的抑制导致有丝分裂途径成分的阻断 [磷酸-Akt (Thr 308)、p65 NF-κB 和 p42/44 Erk 1/2]。总而言之，4-HPR 和 GST 的组合有效地阻断了神经母细胞瘤细胞的存活、促有丝分裂和血管生成途径，并激活了导致细胞凋亡的蛋白酶。这些结果表明，4-HPR 和 GST 的组合可以有效控制异质性人神经母细胞瘤细胞群的生长。
Neuroblastomas, which mostly occur in children, are aggressive metastatic tumors of the sympathetic nervous system. The failure of the previous therapeutic regimens to target multiple components of N-Myc pathway resulted in poor prognosis. The present study investigated the efficacy of the combination of N-(4-hydroxyphenyl) retinamide (4-HPR, 0.5 μM) and genistein (GST, 25 μM) to control the growth of human neuroblastoma cells (SH-SY5Y and SK-N-BE2) harboring divergent molecular attributes. Combination of 4-HPR and GST down regulated N-Myc, Notch-1, and Id2 to induce neuronal differentiation. Transition to neuronal phenotype was accompanied by increase in expression of e-cadherin. Induction of neuronal differentiation was associated with decreased expression of hTERT, PCNA, survivin, and fibronectin. This is the first report that combination of 4-HPR and GST mediated reactivation of multiple tumor suppressors (p53, p21, Rb, and PTEN) for early cell cycle exit (due to G1/S phase arrest) in neuroblastoma cells. Reactivation of tumor suppressor(s) repressed N-Myc driven growth factor mediated angiogenic and invasive pathways (VEGF, b-FGF, MMP-2, and MMP-9) in neuroblastoma. Repression of angiogenic factors led to the blockade of components of mitogenic pathways [phospho-Akt (Thr 308), p65 NF-κB and p42/44 Erk 1/2]. Taken together, the combination of 4-HPR and GST effectively blocked survival, mitogenic, and angiogenic pathways and activated proteases for apoptosis in neuroblastoma cells. These results suggested that combination of 4-HPR and GST could be effective for controlling the growth of heterogeneous human neuroblastoma cell populations.
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影响因子：
11.2
作者：
Chesler, Louis;Goldenberg, David D.;Weiss, William A.
通讯作者：
Weiss, William A.
DOI：
10.1073/pnas.102660199
发表时间：
2002-05-14
影响因子：
11.1
作者：
Jögi, A;Ora, I;Påhlman, S
通讯作者：
Påhlman, S
影响因子：
6.4
作者：
Kikuno, Nobuyuki;Shiina, Hiroaki;Dahiya, Rajvir
通讯作者：
Dahiya, Rajvir
影响因子：
7.3
作者：
Condorelli, F.;Gnemmi, I.;Canonico, P. L.
通讯作者：
Canonico, P. L.
影响因子：
56.9
作者：
HOLLSTEIN, M;SIDRANSKY, D;HARRIS, CC
通讯作者：
HARRIS, CC