ErbB kinases and NDF signaling in human prostate cancer cells
ErbB kinases and NDF signaling in human prostate cancer cells
复制标题
DOI：
10.1038/sj.onc.1201447
复制
发表时间：
1997-11-27
期刊：
影响因子：
8
通讯作者：
Kung, HJ
中科院分区：
文献类型：
--
作者：
Grasso, AW;Wen, DZ;Kung, HJ
前列腺癌(PCA)是美国男性最常见的恶性肿瘤。我们对前列腺癌生长调控的了解落后于其他癌症，如乳腺癌和结肠癌。在受体酪氨酸激酶中，ErbB家族最常与肿瘤有关。我们报道了ErbB家族激酶及其配体在PCa细胞系和异种移植瘤中的表达。ErbB1/EGFR、ErbB2/neu和ErbB3总是以不同的模式出现，但没有观察到ErbB4。有趣的是，尽管转化生长因子-α在大多数前列腺癌细胞系中都有表达，但配体神经分化因子/黑素蛋白(NDF)只在永生化的、未转化的前列腺上皮细胞系中表达。与促进细胞生长的转化生长因子-α相比，NDF抑制LNCaP生长，诱导上皮样形态改变，对这些配体的生物学反应有显著差异。我们还首次对前列腺系中的NDF信号进行了全面的分析，NDF刺激的LNCaP显示ErbB3和ErbB2之间存在串扰，而不涉及ErbB1。NDF还启动了几个级联，包括PI3-K级联、ERK/MAPK级联、mHOG/p38级联和JNK/SAPK级联，但不是PLC伽马级联或STAT家族级联。这种信号模式不同于转化生长因子-α的信号模式。ErbB2或ErbB3对mHOG的激活尚未见报道，这可能是导致这种不寻常表型的原因，PI3-K的激活特征是形成一个显著的‘激活复合体’，其中包括ErbB3。我们的研究为剖析前列腺癌细胞的生长和分化信号提供了一个框架。
Prostate carcinoma (PCA) is the most commonly diagnosed malignancy in American men. Our knowledge of PCA growth regulation lags behind that of other cancers, such as breast and colon carcinomas. Among receptor tyrosine kinases, the ErbB family is most frequently implicated in neoplasia. We report here the expression of ErbB family kinases and their ligands in PCA cell lines and a xenograft. While ErbB1/EGFR, ErbB2/NEU, and ErbB3 were always observed in a distinct pattern, ErbB4 was not observed. Interestingly, while TGF-alpha was expressed in the majority of PCA lines, the ligand Neu Differentiation Factor/Heregulin (NDF) was expressed only in an immortalized, non-transformed prostate epithelial line. Concomitantly, there was a significant difference in biological response to these ligands, NDF inhibited LNCaP growth and induced an epithelial-like morphological change, in contrast to TGF-alpha, which accelerated cell growth. We also performed the first comprehensive analysis of NDF signaling in a prostate line, LNCaP stimulated with NDF demonstrated crosstalk between ErbB3 and ErbB2 which did not involve ErbB1. NDF also turned on several cascades, including those of PI3-K, ERK/MAPK, mHOG/p38 and JNK/SAPK, but not those of PLC gamma or the STAT family. This signaling pattern is distinct from that of TGF-alpha. The activation of mHOG by ErbB2 or ErbB3 has not been reported, and may contribute to the unusual phenotype, PI3-K activation is characterized by the formation of a striking 'activation complex' vith multiple tyrosine-phosphorylated species, including ErbB3. Our studies provide a framework in which to dissect the growth and differentiation signals of prostate cancer cells.