Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways.
Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways.
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DOI：
10.1038/cddis.2014.78
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发表时间：
2014-03-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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目前治疗复发性和侵袭性/间变性甲状腺癌是无效的。旨在抑制突变癌蛋白BRAFV600E的新型靶向治疗在体内和体外都显示出前景，但不会导致细胞凋亡。tnf相关凋亡诱导配体（TRAIL）通过激活外源性凋亡通路，以肿瘤选择性方式诱导细胞凋亡。在这里，我们发现TRAIL-R2激动剂抗体lexatumumab在一些甲状腺癌细胞系（HTh-7， TPC-1和BCPAP）中有效诱导细胞凋亡，而更具侵袭性的间变性细胞系（8505c和SW1736）表现出耐药性。使用lexatumumab联合BRAFV600E抑制剂PLX4720和PI3K抑制剂LY294002（三联用药）治疗最耐药的细胞系8505c，通过在体外触发外源性和内在凋亡途径以及体内触发8505c原位甲状腺肿瘤，使细胞致敏。抗凋亡蛋白pAkt、Bcl-xL、Mcl-1和c-FLIP的减少，加上激活蛋白Bax和Bim的增加，导致Bax与Bcl-xL比率的增加，这似乎对这些耐药细胞的致敏和随后的凋亡至关重要。我们的研究结果表明，靶向甲状腺癌的死亡受体途径可能是诱导甲状腺癌细胞凋亡的一种有希望的策略，尽管在一些最初对凋亡有抗性的更具侵袭性的肿瘤中可能需要与其他激酶抑制剂联合使用。
Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.
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影响因子：
5.7
作者：
Mitsiades, Constantine S.;Negri, Joseph;Mitsiades, Nicholas
通讯作者：
Mitsiades, Nicholas
影响因子：
8
作者：
Giordano, TJ;Kuick, R;Nikiforov, YE
通讯作者：
Nikiforov, YE
影响因子：
6.5
作者：
Berger, Anja;Quast, Sandra-Annika;Eberle, Juergen
通讯作者：
Eberle, Juergen
DOI：
10.1158/1078-0432.ccr-11-3359
发表时间：
2012-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chan CM;Jing X;Pike LA;Zhou Q;Lim DJ;Sams SB;Lund GS;Sharma V;Haugen BR;Schweppe RE
通讯作者：
Schweppe RE
影响因子：
9
作者：
Badmann, A.;Langsch, S.;Corazza, N.
通讯作者：
Corazza, N.