Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice.
Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice.
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DOI：
10.1053/j.gastro.2012.10.036
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发表时间：
2013-02
期刊：
影响因子：
29.4
通讯作者：
Mohammad RM
中科院分区：
文献类型：
--
作者：
Azmi AS;Aboukameel A;Bao B;Sarkar FH;Philip PA;Kauffman M;Shacham S;Mohammad RM
肿瘤抑制蛋白通过许多不同的机制失活，包括通过染色体区域维持（CRM）-1的核排斥。CRM-1的肿瘤水平增加与胰腺癌患者的预后不良相关，使其成为治疗靶点。选择性核输出抑制剂（西内斯）与CRM-1结合，不可逆地抑制其输出蛋白质的能力;我们研究了胰腺癌细胞中的一类新的西内斯。我们使用增殖、凋亡、免疫印迹、免疫共沉淀、小抑制剂（Si）-RNA和荧光显微镜分析研究了SINE类似物在一组胰腺癌细胞系和非转化的人胰腺导管上皮（HPDE）细胞中的作用。还在具有皮下和原位肿瘤的小鼠中研究了西内斯的作用。西内斯（KPT-185、KPT-127、KPT-205和KPT-227）可抑制胰腺癌细胞增殖并促进其凋亡，但对HPDE细胞无影响。用KPT-185孵育的细胞核积累肿瘤抑制蛋白（p27、FOXO、p73和PAR-4），并抑制CRM-1与这些蛋白之间的相互作用。CRM-1与西内斯（Cys-528）结合区域的突变或PAR-4的siRNA敲低阻止了KPT-185阻断胰腺癌细胞增殖和诱导凋亡的能力。小鼠经口给予KPT-330可减少皮下和原位异种移植肿瘤的生长，而无重大毒性。对肿瘤残留物的分析表明，KPT-330破坏了CRM-1和PAR-4之间的相互作用，激活了PAR-4信号传导，并降低了肿瘤细胞的增殖。我们鉴定了抑制CRM-1并促进胰腺癌细胞中肿瘤抑制蛋白的核积累的西内斯。小鼠口服该药物可减少异种移植肿瘤的生长。
Tumor suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells. We studied the effects of SINE analogs in a panel of pancreatic cancer cell lines and non-transformed human pancreatic ductal epithelial (HPDE) cells using proliferation, apoptosis, immunoblot, co-immunoprecipitation, small inhibitor (Si)-RNA, and fluorescence microscopy analyses. The effects of the SINEs were also investigated in mice with subcutaneous and orthotopic tumors. SINEs (KPT-185, KPT-127, KPT-205 and KPT-227) inhibited proliferation and promoted apoptosis of pancreatic cancer cells, but did not affect HPDE cells. The nuclei of cells incubated with KPT-185 accumulated tumor suppressor proteins (p27, FOXO, p73, and PAR-4) and inhibited interactions between CRM-1 and these proteins. Mutations in the region of CRM-1 that binds to SINEs (Cys-528), or siRNA knockdown of PAR-4, prevented the ability of KPT-185 to block proliferation and induce apoptosis of pancreatic cancer cells. Oral administration of KPT-330 to mice reduced growth of subcutaneous and orthotopic xenograft tumors without major toxicity. Analysis of tumor remnants showed that KPT-330 disrupted the interaction between CRM-1 and PAR-4, activated PAR-4 signaling, and reduced proliferation of tumor cells. We identified SINEs that inhibit CRM-1 and promote nuclear accumulation of tumor suppressor proteins in pancreatic cancer cells. Oral administration of the drug to mice reduces growth of xenograft tumors.
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影响因子：
8.4
作者：
Azmi, Asfar S.;Aboukameel, Amro;Banerjee, Sanjeev;Wang, Zhiwei;Mohammad, Momin;Wu, Jack;Wang, Shaomeng;Yang, Dajun;Philip, Philip A.;Sarkar, Fazlul H.;Mohammad, Ramzi M.
通讯作者：
Mohammad, Ramzi M.
影响因子：
64.5
作者：
Fornerod, M;Ohno, M;Mattaj, IW
通讯作者：
Mattaj, IW
影响因子：
8.8
作者：
Newlands, ES;Rustin, GJS;Brampton, MH
通讯作者：
Brampton, MH
影响因子：
8
作者：
Cook, J;Krishnan, S;Rangnekar, VM
通讯作者：
Rangnekar, VM
影响因子：
4.8
作者：
Kudo, N;Taoka, H;Horinouchi, S
通讯作者：
Horinouchi, S