Computational master-regulator search reveals mTOR and PI3K pathways responsible for low sensitivity of NCI-H292 and A427 lung cancer cell lines to cytotoxic action of p53 activator Nutlin-3

作者：Ul'yana A. Boyarskikh, Sergey S. Pintus, Nikita Mandrik, Daria Stelmashenko, Ilya N. Kiselev, Ivan Evshin, Ruslan Sharipov, Philip Stegmaier, Fedor Kolpakov, М. Л. Филипенко, Alexander E Kel · 发表于：BMC Medical Genomics · 年份：2018 · DOI：10.1186/s12920-018-0330-5 · 被引用次数：15 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Cancer-related Molecular Pathways、Sirtuins and Resveratrol in Medicine

BACKGROUND: Small molecule Nutlin-3 reactivates p53 in cancer cells by interacting with the complex between p53 and its repressor Mdm-2 and causing an increase in cancer cell apoptosis. Therefore, Nutlin-3 has potent anticancer properties. Clinical and experimental studies of Nutlin-3 showed that some cancer cells may lose sensitivity to this compound. Here we analyze possible mechanisms for insensitivity of cancer cells to Nutlin-3. METHODS: We applied upstream analysis approach implemented in geneXplain platform ( genexplain.com ) using TRANSFAC® database of transcription factors and their binding sites in genome and using TRANSPATH® database of signal transduction network with associated software such as Match™ and Composite Module Analyst (CMA). RESULTS: Using genome-wide gene expression profiling we compared several lung cancer cell lines and showed that expression programs executed in Nutlin-3 insensitive cell lines significantly differ from that of Nutlin-3 sensitive cell lines. Using artificial intelligence approach embed in CMA software, we identified a set of transcription factors cooperatively binding to the promoters of genes up-regulated in the Nutlin-3 insensitive cell lines. Graph analysis of signal transduction network upstream of these transcription factors allowed us to identify potential master-regulators responsible for maintaining such low sensitivity to Nutlin-3 with the most promising candidate mTOR, which acts in the context of activated PI3K pathway. ...