Abstract
Cisplatin along with other platinum based drugs are some of the most widely used chemotherapeutic agents. However drug resistance is a major problem for the successful chemotherapeutic treatment of cancer. Current evidence suggests that drug resistance is a multifactorial problem due to changes in the expression levels and activity of a wide number of proteins. A majority of the studies to date have quantified mRNA levels between drug resistant and drug sensitive cell lines. Unfortunately mRNA levels do not always correlate with protein expression levels due to post-transcriptional changes in protein abundance. Therefore global quantitative proteomics screens are needed to identify the protein targets that are differentially expressed in drug resistant cell lines. Here we employ a quantitative proteomics technique using stable isotope labeling with amino acids in cell culture (SILAC) coupled with mass spectrometry to quantify changes in protein levels between cisplatin resistant (HeLa/CDDP) and sensitive HeLa cells in an unbiased fashion. A total of 856 proteins were identified and quantified, with 374 displaying significantly altered expression levels between the cell lines. Expression level data was then integrated with a network of protein-protein interactions, and biological pathways to obtain a systems level view of proteome changes which occur with cisplatin resistance. Several of these proteins have been previously implicated in resistance towards platinum-based and other drugs, while many represent new potential markers or therapeutic targets.
Highlights
Many current cancer chemotherapy strategies involve disruption of tumor cell growth by interfering with mitosis or by causing cancer cells to commit to apoptotic pathways
To determine which proteins showed altered expression in HeLa/CDDP compared to HeLa, an analysis of variance (ANOVA) was performed to compare the mean SILAC ratio for each protein from the mixed sample type to the control sample type
In total 387 proteins were found to have significantly shifted expression levels (p,0.01), of which 184 proteins were observed with increased expression levels and 203 proteins were observed with decreased expression levels in HeLa/CDDP
Summary
Many current cancer chemotherapy strategies involve disruption of tumor cell growth by interfering with mitosis or by causing cancer cells to commit to apoptotic pathways. Acquired resistance is the most common reason for cancer chemotherapy failure. Possible mechanisms for resistance to cisplatin include reduced intracellular concentration of cisplatin by increased drug efflux and/or decreased drug influx, increased inactivation by reaction with glutathione and other intracellular nucleophiles, increased repair of DNA damage, and altered apoptotic signaling pathways [1,2]. Cisplatin along with other platinum based drugs such as carboplatin and oxiplatin, are seeing a resurgence of clinical use in combination with other cytotoxic compounds to treat various carcinomas including ovarian, colorectal, prostate, lung and breast cancer [3]
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