CARP-1 functional mimetics: a novel class of small molecule inhibitors of medulloblastoma cell growth.
CARP-1 functional mimetics: a novel class of small molecule inhibitors of medulloblastoma cell growth.
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DOI：
10.1371/journal.pone.0066733
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rishi AK
中科院分区：
文献类型：
--
作者：
Ashour AE;Jamal S;Cheryan VT;Muthu M;Zoheir KM;Alafeefy AM;Abd-Allah AR;Levi E;Tarca AL;Polin LA;Rishi AK
髓母细胞瘤（MBs）是一类侵袭性颅内儿科肿瘤。目前多发性硬化的多模式治疗包括手术、电离辐射和化疗。治疗的毒副作用，加上高复发和转移性扩散的发生率，需要开发更有效、毒性更小的治疗方法。CARP-1/CCAR1是一种核周围磷酸化蛋白，是细胞周期调节后期促进复合物/环体（APC/C） E3连接酶的共激活物。CARP-1功能模拟物（CFMs）是一类新的小分子化合物，它们干扰CARP-1与APC/C亚基APC-2的结合，并部分通过促进细胞凋亡来抑制多种癌细胞的生长。我们研究了CFM-4对MB生长的抑制潜能，发现CFM-4抑制MB细胞生长的部分机制是通过诱导CARP-1表达、促进PARP裂解、激活促凋亡应激激活蛋白激酶（SAPK） p38和JNK以及细胞凋亡。基于基因阵列的分析显示，cfm -4处理的day MB细胞下调了一些关键的细胞生长和转移促进基因，包括调节小GTP结合蛋白p21Rac1的细胞运动和细胞外基质金属肽酶(MMP)-10。此外，CFM-4处理刺激了许多分子的表达，如神经营养因子（NTF）3和NF-κB信号抑制剂ABIN1和2蛋白。过表达NTF3导致MB细胞活力降低，而敲低NTF3则干扰cfm -4依赖性的活力丧失。CFMs还通过阻断MB细胞的迁移能力、在悬浮液中形成菌落和侵入基质包被膜的能力，降低了MB细胞的生物学特性。总之，我们的数据支持CFM-4的抗mb特性，并为cfm作为mb的潜在抗癌药物的进一步开发提供了概念验证基础。
Medulloblastomas (MBs) constitute an aggressive class of intracranial pediatric tumors. Current multimodality treatments for MBs include surgery, ionizing radiation, and chemotherapy. Toxic side effects of therapies coupled with high incidence of recurrence and the metastatic spread warrant development of more effective, less toxic therapies for this disease. CARP-1/CCAR1 is a peri-nuclear phospho-protein that is a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a novel class of small molecule compounds that interfere with CARP-1 binding with APC/C subunit APC-2, and suppress growth of a variety of cancer cells in part by promoting apoptosis. Here we investigated MB growth inhibitory potential of the CFMs and found that CFM-4 inhibits growth of MB cells in part by inducing CARP-1 expression, promoting PARP cleavage, activating pro-apoptotic stress-activated protein kinases (SAPK) p38 and JNK, and apoptosis. Gene-array-based analysis of the CFM-4-treated Daoy MB cells indicated down-regulation of a number of key cell growth and metastasis-promoting genes including cell motility regulating small GTP binding protein p21Rac1, and extracellular matrix metallopeptidase (MMP)-10. Moreover, CFM-4 treatment stimulated expression of a number of molecules such as neurotrophin (NTF)3, and NF-κB signaling inhibitors ABIN1 and 2 proteins. Overexpression of NTF3 resulted in reduced MB cell viability while knock-down of NTF3 interfered with CFM-4-dependent loss of viability. CFMs also attenuated biological properties of the MB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Together our data support anti-MB properties of CFM-4, and provide a proof-of-concept basis for further development of CFMs as potential anti-cancer agents for MBs.
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影响因子：
14.8
作者：
Liang, Chun-Chi;Park, Ann Y.;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
影响因子：
64.8
作者：
Nikoletopoulou, Vassiliki;Lickert, Heiko;Barde, Yves-Alain
通讯作者：
Barde, Yves-Alain
影响因子：
5.3
作者：
Karl S;Pritschow Y;Volcic M;Häcker S;Baumann B;Wiesmüller L;Debatin KM;Fulda S
通讯作者：
Fulda S
DOI：
10.2741/1016
发表时间：
2003-01-01
期刊：
FRONTIERS IN BIOSCIENCE
影响因子：
--
作者：
Nakada, M;Okada, Y;Yamashita, J
通讯作者：
Yamashita, J
影响因子：
16
作者：
Liu, J;Yang, D;Lin, A
通讯作者：
Lin, A