Liu Xunxian, Allen Jeffrey D, Arnold Julia T, Blackman Marc R
Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
Carcinogenesis. 2008 Apr;29(4):816-23. doi: 10.1093/carcin/bgn011. Epub 2008 Feb 17.
Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.
前列腺基质细胞与上皮细胞之间的通讯在前列腺功能及癌症发展过程中起着重要作用。源自正常前列腺基质细胞（PRSC）的原代人基质细胞维持平滑肌表型，而源自前列腺癌的基质细胞（6S）则表现出反应性和成纤维细胞特征。双氢睾酮（DHT）可刺激6S细胞产生胰岛素样生长因子-I（IGF-I），但对PRSC细胞无此作用。关于反应性基质与正常基质对正常人前列腺上皮（NPE或PREC）细胞的影响，目前了解甚少。我们将NPE细胞与6S或PRSC细胞进行共培养，以比较不同基质细胞对正常上皮细胞的影响。由于NPE和PREC细胞在培养过程中会失去雄激素受体（AR）表达，因此DHT的作用必须由相关基质细胞进行调节。当用喜树碱（CM）处理时，单独培养以及与基质细胞共培养的NPE细胞均表现出DNA片段化呈剂量依赖性增加。NPE/6S共培养物在暴露于DHT时，CM诱导的细胞死亡减少，而NPE/PRSC共培养物无论是否接受DHT处理，均表现出CM诱导的细胞死亡。在共培养的NPE/6S细胞中，DHT可阻断CM诱导的、IGF-I介导的NPE细胞死亡，但添加抗IGF-I和抗IGF-R抗体后则无此作用。番茄红素的摄入量与人类前列腺癌风险呈负相关，并且可抑制大鼠前列腺癌中的IGF-I和雄激素信号传导。在本研究中，饮食浓度的番茄红素可逆转6S细胞的DHT对NPE细胞死亡的影响，通过减少AR和β-连环蛋白的核定位来降低6S细胞IGF-I的产生，并抑制IGF-I刺激的NPE和PREC生长，这可能是通过减弱IGF-I对Akt和GSK3β丝氨酸磷酸化以及GSK3酪氨酸磷酸化的作用来实现的。本研究扩展了对番茄红素在前列腺癌预防机制方面的认识。
