Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines.
Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines.
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DOI：
10.1371/journal.pone.0061256
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Langenfeld J
中科院分区：
文献类型：
--
作者：
Langenfeld E;Hong CC;Lanke G;Langenfeld J
骨形态发生蛋白（BMP）是高度保守的形态发生素，对于正常发育至关重要。 BMP-2 在大多数非小细胞肺癌 (NSCLC) 中高表达，但在正常肺组织或良性肺肿瘤中不表达。 BMP 信号级联对癌细胞生长和存活的影响尚不清楚。我们发现 BMP 信号传导在肺癌细胞系中具有基础活性，可以用 BMP I 型受体的选择性拮抗剂有效抑制。肺癌细胞系表达 alk2、alk3 和 alk6，并且抑制单个 BMP 受体不足以减少信号传导。需要抑制不止一种 I 型受体才能减少肺癌细胞系中的 BMP 信号传导。 BMP 受体拮抗剂和用 siRNA 沉默 BMP I 型受体可诱导细胞死亡、抑制细胞生长，并导致分化抑制剂（Id1、Id2 和 Id3）家族成员的表达显着下降，已知这些成员在多种癌症中调节细胞生长和存活。 BMP 受体拮抗剂还可以减少克隆细胞的生长。 Id3 的敲低显着降低了肺癌细胞的细胞生长并诱导细胞死亡。稳定过表达Id3的H1299细胞对BMP拮抗剂DMH2诱导的生长抑制和细胞死亡诱导具有抵抗力。这些研究表明，BMP 信号传导促进肺癌细胞的细胞生长和存活，这是通过其对 Id 家族成员的调节来介导的。 BMP I 型受体的选择性拮抗剂代表了通过激活的 BMP 信号级联对 NSCLC 和其他癌症进行药理学治疗的潜在方法。
Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.
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DOI：
10.1158/1078-0432.ccr-08-2362
发表时间：
2010-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lin J;Guan Z;Wang C;Feng L;Zheng Y;Caicedo E;Bearth E;Peng JR;Gaffney P;Ondrey FG
通讯作者：
Ondrey FG
影响因子：
2.9
作者：
KE, Y;REDDEL, RR;HARRIS, CC
通讯作者：
HARRIS, CC
影响因子：
8
作者：
Gray, M. J.;Dallas, N. A.;Van Buren, G.;Xia, L.;Yang, A. D.;Somcio, R. J.;Gaur, P.;Mangala, L. S.;Vivas-Mejia, P. E.;Fan, F.;Sanguino, A. M.;Gallick, G. E.;Lopez-Berestein, G.;Sood, A. K.;Ellis, L. M.
通讯作者：
Ellis, L. M.
影响因子：
4.7
作者：
Langenfeld, EM;Calvano, SE;Langenfeld, J
通讯作者：
Langenfeld, J
影响因子：
10.5
作者：
Lawson, KA;Dunn, NR;Hogan, BLM
通讯作者：
Hogan, BLM