Project description:HGF sensitizes ovarian cancer cells to chemotherapeutics, e.g. cisplatin (CDDP), through a signaling cascade activated by its MET oncogene encoded receptor and transduced by the p38MAPK. This cascade results in the regulation of a common set of transcripts in three ovarian cancer cell lines, with different genetic profiles and susceptibility to drugs. In order to elucidate the mechanism of HGF dependent cell sensitization to drugs, the transcriptional response of the three ovarian cancer cell lines to HGF and CDDP were studied by microarray based transcription profiling
Project description:Advanced ovarian cancers are initially responsive to chemotherapy with platinum drugs but develop drug resistance in most cases. We showed recently that hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and that this effect is mediated by the p38 mitogen-activated protein kinase. In this work, we integrated genome-wide expression profiling, in silico data survey, and functional assays to identify transcripts regulated in SK-OV-3 ovarian cancer cells made more responsive to CDDP by HGF. Using oligonucleotide microarrays, we found that HGF pretreatment changes the transcriptional response to CDDP. Quantitative reverse transcription-PCR not only validated all the 15 most differentially expressed genes but also confirmed that they were primarily modulated by the combined treatment with HGF and CDDP and reversed by suppressing p38 mitogen-activated protein kinase activity. Among the differentially expressed genes, we focused functional analysis on two regulatory subunits of the protein phosphatase 2A, which were down-modulated by HGF plus CDDP. Decrease of each subunit by RNA interference made ovarian cancer cells more responsive to CDDP, mimicking the effect of HGF. In conclusion, we show that HGF and CDDP modulate transcription in ovarian cancer cells and that this transcriptional response is involved in apoptosis regulation. We also provide the proof-of-concept that the identified genes might be targeted to either increase the efficacy of chemotherapeutics or revert chemotherapy resistance.
Project description:The transcriptional response to CDDP of three ovarian cancer cell lines was studied. These lines show different genetic profiles and display different susceptibilities to CDDP. The time and doses that resulted in the apoptotic death of each cell line was identified and used to study the expression profiles associated to CDDP-induced cell death in each cell line. CDDP: cis-diamminedichloroplatinum(II) In order to elucidate the mechanism of CDDP dependent cell susceptibilities to drugs, the transcriptional response of the three ovarian cancer cell lines to CDDP were studied by microarray based transcription profiling
Project description:HGF sensitizes ovarian cancer cells to chemotherapeutics, e.g. cisplatin (CDDP), through a signaling cascade activated by its MET oncogene encoded receptor and transduced by the p38MAPK. This cascade results in the regulation of a common set of transcripts in three ovarian cancer cell lines, with different genetic profiles and susceptibility to drugs.
Project description:The transcriptional response to CDDP of three ovarian cancer cell lines was studied. These lines show different genetic profiles and display different susceptibilities to CDDP. The time and doses that resulted in the apoptotic death of each cell line was identified and used to study the expression profiles associated to CDDP-induced cell death in each cell line. CDDP: cis-diamminedichloroplatinum(II)
Project description:To investigate the main mechanism underlying cisplatin resistance in ovarian cancer, A2780/CDDP and SKOV3/CDDP cell lines were treated with both maggot extracts and cisplatin. We then performed gene expression profiling analysis using data obtained from RNA-seq of A2780 and A2780/CDDP cells.