A proteomic kinetic analysis of IGROV1 ovarian carcinoma cell line response to cisplatin treatment

Abstract

Ovarian cancer is one of the leading causes of mortality by gynecological cancer. Despite good response to surgery and initial chemotherapy, essentially based on cisplatin (cis-diamino-dichloro-platinum(II) (CDDP)) compounds, frequent recurrences with chemoresistance acquisition are responsible for poor prognosis. Several mechanisms have been described as implicated in CDDP resistance, however they are not sufficient to exhaustively account for this resistance emergence. We applied a proteomic approach based on 2-DE coupled with MS (MALDI-TOF/TOF) to identify proteins associated with chemoresistance induced by CDDP. A kinetic analysis of IGROV1 cell behavior following treatment with CDDP and subsequent statistical analysis revealed time and/or concentration-dependent modifications in protein expression. We evidenced events such as decreased amino-acid and nucleotide synthesis potentially associated with cell cycle blockade, and variations that may be related to resistance acquisition, such as possible enhanced glycolysis and increased proliferating potential. Moreover, overexpressions of aldehyde dehydrogenase 1 and both cytokeratins 8 and 18 were consistent with our previous findings, demonstrating that expression of these proteins was increased in cisplatin-resistant IGROV1-R10 as compared to IGROV1 parental cells. Identification of such proteins could allow improved understanding of the mechanisms leading to cell death or survival and, thus, to the acquisition of chemoresistance.

The molecular mechanisms of antimetastatic ruthenium compounds explored through DIGE proteomics

“…Apparently, there is a very poor match between proteins responding to ruthenium compounds and those which respond to cisplatin treatment that were identified in previous proteomic studies [27][28][29][30][31]. This observation suggests that the cellular effects and the mode of action of these anticancer ruthenium drugs are profoundly different from those of clinically established, DNA damaging, platinum compounds in line with other literature reports.…”

Quantitative Proteomics Analysis Integrated with Microarray Data Reveals That Extracellular Matrix Proteins, Catenins, and P53 Binding Protein 1 Are Important for Chemotherapy Response in Ovarian Cancers

“…Mass-spectrometry-based quantitative proteomics, such as the isotope-coded affinity tags (ICAT) labeling (Gygi et al, 1999) combined with liquid chromatography (LC)-tandem mass spectrometer (MS=MS), allow global identification and quantification of proteins in complex samples and are well suited for discovering potential biomarkers for human diseases (Aebersold et al, 2005;Aebersold and Mann, 2003). We and others have used ovarian cancer cell line models such as IGROV1 and GROV1-CP cells to identify proteins related to chemotherapy responses (Le Moguen et al, 2007;Stewart et al, 2006). However, to our knowledge, a direct proteomics analysis using ovarian cancer tissues from chemotherapy-resistant and chemotherapy-sensitive tissues has not yet been performed, probably due to difficulties in obtaining necessary tissues with clinically defined chemotherapy response statuses as lengthy follow-up is needed to ascertain responsiveness to chemotherapy drugs.…”

Proteomics of ovarian cancer: functional insights and clinical applications

“…examined multiple drug resistance in ovarian cancer cell lines using iTRAQ LC-MS/MS and identified 28 protein markers that might contribute to cisplatin resistance, which were then classified into eight categories: calcium-binding proteins, chaperones, extracellular matrix, proteins involved in drug detoxification or repair of DNA damage, metabolic enzymes, transcription factor, proteins related to cellular structure, and proteins relative to signal transduction [91]. Other mechanisms of drug resistance related to stress response, metabolism, and cell cycle and apoptosis have been revealed by other proteomic studies [95, 98, 99]. …”