Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells.
Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells.
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DOI：
10.1016/j.canlet.2017.09.033
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发表时间：
2017-12-28
期刊：
影响因子：
9.7
通讯作者：
Williams KP
中科院分区：
文献类型：
--
作者：
Oladapo HO;Tarpley M;Sauer SJ;Addo KA;Ingram SM;Strepay D;Ehe BK;Chdid L;Trinkler M;Roques JR;Darr DB;Fleming JM;Devi GR;Williams KP
Hedgehog（Hh）通路效应物GLI 1的激活与许多癌症的肿瘤发生和侵袭性有关，小分子拮抗剂靶向GLI 1显示出有效性。我们分析了一组GLI拮抗剂，这些拮抗剂在炎性和非炎性乳腺癌（IBC和非IBC）的表型模型中具有不同的疗效作用机制，我们显示表达不同水平的Hh通路介质。化合物GANT 61、HPI-1和JK 184降低了TN-IBC（SUM 149）和TNBC（MDA-MB-231和SUM 159）细胞系中的细胞增殖，抑制了GLI 1 mRNA表达，并降低了形成的集落数。此外，GANT 61和JK 184显著下调了调节细胞周期（细胞周期蛋白D和E）和凋亡（Bcl 2）的GLI 1靶标。GANT 61减少了SUM 149球体生长和栓塞形成，并且在原位SUM 149肿瘤模型中显著降低了肿瘤生长。我们成功地利用表型分析，以确定一个子集的GLI 1拮抗剂，优先在体内模型中进行测试。我们的研究结果表明，TN-IBC中的GLI 1活化与TNBC中一样，在促进细胞增殖、运动、肿瘤生长和肿瘤栓塞形成中起着至关重要的作用。
Activation of the Hedgehog (Hh) pathway effector GLI1 is linked to tumorigenesis and invasiveness in a number of cancers, with targeting of GLI1 by small molecule antagonists shown to be effective. We profiled a collection of GLI antagonists possessing distinct mechanisms of action for efficacy in phenotypic models of inflammatory and non-inflammatory breast cancer (IBC and non-IBC) that we showed expressed varying levels of Hh pathway mediators. Compounds GANT61, HPI-1, and JK184 decreased cell proliferation, inhibited GLI1 mRNA expression and decreased the number of colonies formed in TN-IBC (SUM149) and TNBC (MDA-MB-231 and SUM159) cell lines. In addition, GANT61 and JK184 significantly down-regulated GLI1 targets that regulate cell cycle (cyclin D and E) and apoptosis (Bcl2). GANT61 reduced SUM149 spheroid growth and emboli formation, and in orthotopic SUM149 tumor models significantly decreased tumor growth. We successfully utilized phenotypic profiling to identify a subset of GLI1 antagonists that were prioritized for testing in in vivo models. Our results indicated that GLI1 activation in TN-IBC as in TNBC, plays a vital role in promoting cell proliferation, motility, tumor growth, and formation of tumor emboli.
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影响因子：
8.8
作者：
Forozan, F;Veldman, R;Ammerman, CA;Parsa, NZ;Kallioniemi, A;Kallioniemi, OP;Ethier, SP
通讯作者：
Ethier, SP
影响因子：
4.8
作者：
Das, Shamik;Harris, Lillianne G.;Shevde, Lalita A.
通讯作者：
Shevde, Lalita A.
影响因子：
9.7
作者：
Fu, Junsheng;Rodova, Mariana;Roy, Sanjit K.;Sharma, Jay;Singh, Karan P.;Srivastava, Rakesh K.;Shankar, Sharmila
通讯作者：
Shankar, Sharmila
影响因子：
--
作者：
Agyeman A;Jha BK;Mazumdar T;Houghton JA
通讯作者：
Houghton JA
影响因子：
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作者：
Benvenuto M;Masuelli L;De Smaele E;Fantini M;Mattera R;Cucchi D;Bonanno E;Di Stefano E;Frajese GV;Orlandi A;Screpanti I;Gulino A;Modesti A;Bei R
通讯作者：
Bei R