A COMPARATIVE PROTEOMIC ANALYSIS OF MITOCHONDRIAL PROTEINS FROM DRUG SUSCEPTIBLE AND DRUG RESISTANT HUMAN MCF-7 BREAST CANCER CELLS

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2005-06-01

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Abstract

Cancer is a leading cause of death in the United States. Chemotherapy is often used in treatment of the disease; however, it often fails as a result of the development of drug resistance. To improve patient outcome and develop more effective chemotherapeutic agents, it is necessary to better understand the mechanisms responsible for the development of drug resistance. In order to identify mitochondrial proteins that may contribute to drug resistance a comparative proteomic analysis has been performed. Specifically, mitochondria were isolated from a drug susceptible and two drug resistant human MCF-7 breast cancer cell lines. The soluble proteins were extracted and separated by two-dimensional gel electrophoresis. Proteins were identified by mass spectrometry combined with bioinformatics. Comparative densitometry of the gel images was used to determine the relative quantitation of each protein.

One hundred and fifty three unique proteins have been identified in this analysis. Of these, fifteen proteins were found to be significantly more or less abundant between the drug susceptible MCF-7 cell line and the MCF-7 cell lines selected for resistance to adriamycin in the presence of verapamil and to mitoxantrone. In both resistant cell lines, proteins involved in oxidative phosphorylation were shown to have altered abundances. Additional proteins whose abundances changed were detected in the adriamycin resistant cell line. These proteins play a role in several mitochondrial pathways including fatty acid oxidation, heme biosynthesis and apoptosis. Based on our analysis, we conclude that mechanisms responsible for drug resistance are different for adriamyin and mitoxantrone. In addition, we have proposed novel mechanims of resistance for some of these proteins.

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