Human colorectal cancer cell lines treated with several inhibitors of PI3Kinase – AKT signaling pathway
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE18005 | GEO | 2010/06/14
SECONDARY ACCESSION(S): PRJNA119905
REPOSITORIES: GEO
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Project description:Signal transduction processes mediated by phosphatidyl inositol phosphates affect a broad range of cellular processes such as cell cycle progression, migration and cell survival. The protein kinase AKT is one of the major effectors in this signaling network. Chronic AKT activation contributes to oncogenic transformation and tumor development. Therefore, new small drugs were designed to block AKT activity for cancer treatment. Here we characterize the biological effects of the phosphatidyl inositol phosphate analogs SH-5 and SH-6 in colorectal cancer cell lines. We demonstrate that the two compounds did not reduce AKT phosphorylation significantly in the presence of growth factors, but induce a broad range of morphological and transcriptional alterations. Transcriptomic profiling in inhibitor-treated SW480 cells revealed a cluster of down- regulated genes associated with mitosis. Moreover, the treatment of SW480 cells with either SH-5 or SH-6 caused the formation of binucleated cells as a result of a specific abscission defect. The cells were treated with certain inhibitors for 48 hours. We used one sample per cell line treated with DMSO as a control, and one sample for each of the treatments.
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Project description:Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with a 5 year-survival rate below 5%. Lack of curative treatment and failure of targeted therapies urge the need to identify novel efficient therapeutic strategy. Achievement of this goal will be obtained through the identification of diagnosis and prognosis biomarkers, identification of novel therapeutic targets and the knowledge of resistance mechanisms induced by these targeted therapies. PI3K/Akt/mTOR signalling, one of the most altered in cancers, is overactivated in pancreatic cancer and correlated with poor prognosis. In the Vertebrates, the family of class I phosphoinoitide-3-kinase (PI3K) includes four isoforms: p110α, p110β, p110δ and p110γ. Although they all perform the same biochemical reaction (phosphorylation of PIP2 in PIP3, a membrane lipid messenger), each isoform were demonstrated to have specific physiological roles. Global PI3K inhibitors are currently being tested in phase I/II clinical trials in advanced solid cancers, but show at maximal doses tolerated a limited therapeutic benefit. Isoform-selective PI3K inhibitors are currently the most promising agents because, at low doses, they are more efficient to inhibit one PI3K isoform, and thus, less toxic than pan-PI3K inhibitors. The objectives of this thesis are to determine isoform-specific PI3K roles and the therapeutic interest to target one or more isoforms in pancreatitis and PDAC, by the identification of isoform-specific pathways and the study of adaptive responses induced by targeting of one or all isoforms of PI3K. In a first part, my work has highlighted, validated and completed results obtained in the team, to demonstrate the significance of PI3K/Akt signalling in two physiological processes: chronic pancreatitis and initiation of pancreatic carcinogenesis. Precisely, the overactivation of PI3K/Akt pathway measured on human and murine chronic pancreatitis samples is correlated with a specific p110α activation gene expression signature. Moreover, genetic and pharmacologic inactivation of p110α during pancreatic chronic inflammation or cancerogenesis (by oncogenic Kras) prevents the formation of acino-ductal metaplasia, structures at the origin of pancreatic carcinogenesis initiation. Development of in vitro acino-ductal transdifferentiation protocol allowed me to demonstrate that only p110α is necessary at this initial step of pancreatic carcinogenesis by the regulation of Rho small GTPases, further regulating actin remodelling. In the second part, by a phosphoproteomic-based approach, I quantified PI3K downstream phosphorylation-regulated targets in a pancreatic cancer cell line treated or not by a pan- or selective PI3K inhibitor at different times. I demonstrated for the first time existence of targets, signalling pathways and adaptive responses regulated by each PI3K isoform. To conclude, all these results demonstrate the rational of combinatorial use of isoform-specific PI3K inhibitors in patients with pancreatic cancer for better clinical response
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Project description:Transgenic Arabidopsis plants with constitutively low inositol (1,4,5) triphosphate exhibit an increased tolerance to water stress by an ABA-independent pathway The phosphoinositide pathway and inositol (1,4,5) trisphopsphate (InsP3) are implicated in plant responses to stress. In order to manipulate the pathway and determine the downstream consequences of altered InsP3-mediated signaling, we generated transgenic Arabidopsis plants expressing the mammalian type I inositol polyphosphate 5-phosphatase, an enzyme that specifically hydrolyzes the soluble inositol phosphates and terminates the signal. Transgenic plants have no morphological differences compared to wild type; however, rapid transient Ca2+ responses to a cold or salt stimulus are reduced by ~ 30%. To further understand the role of InsP3-mediated signaling in plant stress responses we focused on drought stress. Surprisingly, the InsP 5-ptase plants lose less water and exhibited an increased tolerance to drought. Stomatal bioassays showed that transgenic guard cells are less responsive to the inhibition of opening by ABA but show an increased sensitivity to ABA-induced closure. The onset of the drought stress is delayed in the transgenic plants and ABA levels did not increase as much as in the wild type. Transcript profiling has revealed that DREB2A and a subset of DREB2A regulated genes are basally up regulated in the InsP 5-ptase plants. These results indicate that the drought tolerance of the InsP 5-ptase plants is mediated in part via an ABA-independent pathway. The constitutive dampening of the InsP3 signal in this system has uncovered novel regulation and cross talk between signaling pathways. Keywords: drought stress, expression study
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