Grasso A W, Wen D, Miller C M, Rhim J S, Pretlow T G, Kung H J
Case Western Reserve University School of Medicine, Department of Molecular Biology and Microbiology, Cleveland, Ohio 44106-4960, USA.
Oncogene. 1997 Nov 27;15(22):2705-16. doi: 10.1038/sj.onc.1201447.
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 PLCgamma 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' with multiple tyrosine-phosphorylated species, including ErbB3. Our studies provide a framework in which to dissect the growth and differentiation signals of prostate cancer cells.
前列腺癌（PCA）是美国男性中最常被诊断出的恶性肿瘤。我们对PCA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家族最常与肿瘤形成有关。我们在此报告ErbB家族激酶及其配体在PCA细胞系和异种移植中的表达情况。虽然总是以独特模式观察到ErbB1/表皮生长因子受体（EGFR）、ErbB2/神经表皮生长因子受体（NEU）和ErbB3，但未观察到ErbB4。有趣的是，虽然大多数PCA细胞系中都表达转化生长因子-α（TGF-α），但配体神经分化因子/神经调节蛋白（NDF）仅在永生化、未转化的前列腺上皮细胞系中表达。同时，对这些配体的生物学反应存在显著差异。与加速细胞生长的TGF-α相反，NDF抑制LNCaP细胞生长并诱导上皮样形态变化。我们还对前列腺细胞系中的NDF信号传导进行了首次全面分析。用NDF刺激的LNCaP细胞显示出ErbB3和ErbB2之间的相互作用，其中不涉及ErbB1。NDF还激活了几个信号级联反应，包括磷脂酰肌醇-3激酶（PI3-K）、细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK/MAPK）、丝裂原活化蛋白激酶激酶/ p38（mHOG/p38）和应激活化蛋白激酶/ c-Jun氨基末端激酶（JNK/SAPK）的信号级联反应，但不包括磷脂酶Cγ（PLCγ）或信号转导和转录激活因子（STAT）家族的信号级联反应。这种信号传导模式与TGF-α不同。ErbB2或ErbB3激活mHOG的情况尚未见报道，这可能导致了这种异常表型。PI3-K的激活特征是形成一个由多个酪氨酸磷酸化物种组成的显著“激活复合物”，包括ErbB3。我们的研究提供了一个剖析前列腺癌细胞生长和分化信号的框架。
