Stewart Jennifer J, White James T, Yan Xiaowei, Collins Steven, Drescher Charles W, Urban Nicole D, Hood Leroy, Lin Biaoyang
The Institute for Systems Biology, Seattle, Washington 98103, USA.
Mol Cell Proteomics. 2006 Mar;5(3):433-43. doi: 10.1074/mcp.M500140-MCP200. Epub 2005 Nov 30.
Nearly all women diagnosed with ovarian cancer receive combination chemotherapy including cis- or carboplatin. Despite high initial response rates, resistance to cisplatin develops in roughly one-third of women during primary treatment and in all women treated for recurrent disease. ICAT coupled with tandem MS is a quantitative proteomic technique for high throughput protein expression profiling of complex protein mixtures. Using ICAT/MS/MS we profiled the nuclear, cytosolic, and microsomal fractions obtained from IGROV-1 [corrected] (cisplatin-sensitive) and IGROV-1/CP [corrected] (cisplatin-resistant) ovarian cancer cell lines. The proteomes of cisplatin-sensitive and -resistant ovarian cancer cells were compared, and protein expression was correlated with mRNA expression profiles. A total of 1117 proteins were identified and quantified. The relative expression of 121 of these varied between the two cell lines. Sixty-three proteins were overexpressed in cisplatin-sensitive, and 58 were over expressed in cisplatin-resistant cells. Examples of proteins at least 5-fold overexpressed in resistant cells and with biological relevance to cancer include cell recognition molecule CASPR3 (13.3-fold), S100 protein family members (8.7-fold), junction adhesion molecule Claudin 4 (7.2-fold), and CDC42-binding protein kinase beta (5.4-fold). Examples of cancer-related proteins at least 5-fold overexpressed in sensitive cells include hepatocyte growth factor inhibitor 1B (13.3-fold) and programmed cell death 6-interacting protein (12.7-fold). The direction of changes in expression levels between proteins and mRNAs were not always in the same direction, possibly reflecting posttranscriptional control of protein expression. We identified proteins whose expression profiles correlate with cisplatin resistance in ovarian cancer cells. Several proteins may be involved in modulating response to cisplatin and have potential as markers of treatment response or treatment targets.
几乎所有被诊断出患有卵巢癌的女性都会接受包括顺铂或卡铂在内的联合化疗。尽管初始缓解率很高，但在初次治疗期间，约三分之一的女性会对顺铂产生耐药性，而在接受复发性疾病治疗的所有女性中都会出现这种情况。ICAT与串联质谱联用是一种用于对复杂蛋白质混合物进行高通量蛋白质表达谱分析的定量蛋白质组学技术。我们使用ICAT/MS/MS对从IGROV-1（顺铂敏感）和IGROV-1/CP（顺铂耐药）卵巢癌细胞系中获得的细胞核、细胞质和微粒体部分进行了分析。比较了顺铂敏感和耐药卵巢癌细胞的蛋白质组，并将蛋白质表达与mRNA表达谱进行了关联。总共鉴定并定量了1117种蛋白质。其中121种蛋白质的相对表达在两种细胞系之间有所不同。63种蛋白质在顺铂敏感细胞中过度表达，58种在顺铂耐药细胞中过度表达。在耐药细胞中至少5倍过度表达且与癌症具有生物学相关性的蛋白质示例包括细胞识别分子CASPR3（13.3倍）、S100蛋白家族成员（8.7倍）、连接粘附分子Claudin 4（7.2倍）和CDC42结合蛋白激酶β（5.4倍）。在敏感细胞中至少5倍过度表达的癌症相关蛋白质示例包括肝细胞生长因子抑制剂1B（13.3倍）和程序性细胞死亡6相互作用蛋白（12.7倍）。蛋白质和mRNA表达水平变化的方向并不总是相同的，这可能反映了蛋白质表达的转录后调控。我们鉴定出了其表达谱与卵巢癌细胞中顺铂耐药性相关的蛋白质。几种蛋白质可能参与调节对顺铂的反应，并具有作为治疗反应标志物或治疗靶点的潜力。
