Proteins Associated with Cisplatin Resistance in Ovarian Cancer Cells Identified by Quantitative Proteomic Technology and Integrated with mRNA Expression Levels

• DOI: 10.1074/mcp.m500140-mcp200
• Publication Date: 2005-12-01T01:44:19Z
• Authors: Jennifer J. Stewart; James T. White; Xiaowei Yan; Steven Collins; Charles W. Drescher; Nicole D. Urban; Leroy Hood; Biaoyang Lin
• Keywords: Ovarian Neoplasms; Proteomics; 0301 basic medicine; Protein Array Analysis; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Drug Therapy; Drug Resistance, Neoplasm; Cell Line, Tumor; Tumor Cells, Cultured; Humans; Female; RNA, Messenger; Cisplatin; Genes, Neoplasm

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.