Nagano Kohji, Masters John R, Akpan Akunna, Yang Alice, Corless Steve, Wood Chris, Hastie Claire, Zvelebil Marketa, Cramer Rainer, Naaby-Hansen Soren
Ludwig Institute for Cancer Research, Royal Free and University College London Medical School, London, UK.
Oncogene. 2004 Mar 4;23(9):1693-703. doi: 10.1038/sj.onc.1207297.
Protein expression and de novo synthesis in normal and prostate cancer cell lines derived from the same patient were compared by proteomic analysis, and the effects of INFalpha and INFgamma (INF=interferon) determined. The expressions of several INF-inducible proteins, including MxA, Nmi, PA28a and IFP53, were downregulated in the cancer cells. INFgamma induced a more than twofold increase or decrease in the synthesis rates of almost twice as many proteins in the cancer cell line. The positive regulator of INF-induced transcription ISGF3gamma was upregulated in the cancer cells and inversely regulated by INFalpha and INFgamma in the normal and cancer cells. Moreover, ISGF3gamma's induction by INFgamma in the cancer cells was more enhanced by simultaneous stimulation with EGF, than its induction in the normal cells. In all, 31 differentially regulated proteins were identified by mass spectrometry analysis, several of which are involved in chaperone-assisted protein folding in the endoplasmic reticulum (ER) or in regulated protein degradation. Our results suggest that the exclusion of proteins by the ER quality control system, crosstalk between the EGF- and INF-induced signalling pathways and the regulation of INF-inducible genes are all altered in the prostate cancer cells. The combination of upregulated activity in the growth-promoting PI3K/Akt pathway, suppression of Nmi and overexpression of hnRNP-K and c-myc proteins may explain why the prostate cancer cells were found to be more resistant to the growth inhibitory effects of INFgamma.
通过蛋白质组学分析比较了源自同一患者的正常和前列腺癌细胞系中的蛋白质表达及从头合成情况，并确定了INFα和INFγ（INF = 干扰素）的作用。包括MxA、Nmi、PA28α和IFP53在内的几种INF诱导蛋白在癌细胞中的表达下调。在癌细胞系中，INFγ诱导合成速率增加或降低两倍以上的蛋白质数量几乎是正常细胞系中的两倍。INF诱导转录的正调节因子ISGF3γ在癌细胞中上调，且在正常细胞和癌细胞中受到INFα和INFγ的反向调节。此外，与正常细胞相比，在癌细胞中，EGF同时刺激可增强INFγ对ISGF3γ的诱导作用。通过质谱分析共鉴定出31种差异调节蛋白，其中几种参与内质网（ER）中伴侣蛋白辅助的蛋白质折叠或调节性蛋白质降解。我们的结果表明，前列腺癌细胞中内质网质量控制系统对蛋白质的排除、EGF和INF诱导的信号通路之间的串扰以及INF诱导基因的调控均发生了改变。生长促进性PI3K/Akt途径活性上调、Nmi抑制以及hnRNP-K和c-myc蛋白过表达的共同作用，可能解释了为何前列腺癌细胞对INFγ的生长抑制作用更具抗性。
