COMPARATIVE PROTEOMICS STUDIES OF SOLUBLE NUCLEAR PROTEINS OF DRUG SUSCEPTIBLE AND RESISTANT HUMAN BREAST CANCER MCF-7 CELLS
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Drug resistance is a major obstacle in cancer chemotherapy. Better understanding of the mechanisms of the drug resistance can help to improve clinical treatment and develop new drugs. Since most anticancer drugs target the nuclei of the cancer cells, differential expression of nuclear proteins may play crucial roles as cancer cells acquire drug resistance. Thus I have carried out a comparative proteomics research project to study differential expression of nuclear proteins in drug resistant human breast cancer MCF-7 cells. Two dimensional gel electrophoresis and stable isotope labeling by amino acids in cell culture are used to conduct the study. Protein identification is acquired by peptide fingerprinting or microsequencing. Relative quantitation of the proteins is derived from gel comparisons and from ratios of labeled and unlabeled peptide pairs. A drug susceptible MCF-7 cell line and four drug resistant MCF-7 cell lines were examined. The drug resistant cell lines are resistant to different chemotherapeutic drugs and are well characterized. The known mechanisms of drug resistance can not satisfactorily answer how the drug resistance is conferred. One hundred and twenty proteins have been identified from the nuclear protein mixture of MCF-7 cells, from which more than 90% are classically categorized as nuclear proteins. Fourteen proteins are found to be significantly less or more abundant (more than 2 fold) in MCF-7 breast cancer cell lines resistant to etoposide, mitoxantrone, adriamycin in the presence of verapamil by both gel comparisons and isotope labeling. Abundances of cytoskeleton proteins, such as cytokeratin 8, cytokeratin 19, septin 2, and alpha tropomyosin, are altered in common across the three resistant cell lines. MCF-7 cell lines resistant to etoposide and mitoxantrone are more similar in protein abundance changes. Some of the proteins whose abundances are altered have also been reported to play important roles in resisting genotoxic stress in other normal and cancer cells. Their potential mechanistic contributions to drug resistance and implications for genetic regulation are discussed.