Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

Isinger-Ekstrand, Anna; Jönsson, Mats; Lindblom, Annika; Borg, Åke; Nilbert, Mef

doi:10.1007/s10689-009-9293-1

Cited by 51 publications

(36 citation statements)

References 28 publications

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“…mTOR is a member of the PI3K/AKT/mTOR pathway, whose activation stimulates protein and lipid biosynthesis and it is constitutively activated in LS (43). The mTOR signaling pathway senses and integrates a variety of environmental cues to regulate numerous major cellular processes (44,45).…”

Section: Discussionmentioning

confidence: 99%

Hsa-miR-137, hsa-miR-520e and hsa-miR-590-3p perform crucial roles in Lynch syndrome

Zhou

et al. 2016

Oncology Letters

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Abstract. The aim of the present study was to identify the differentially expressed microRNAs (DEMs) between Lynch syndrome (LS) and the normal colonic (N-C) control samples, predict the target genes (TGs) and analyze the potential functions of the DEMs and TGs. The miRNA expression dataset GSE30454, which included data of 13 LS and 20 N-C tissue samples, was downloaded from the Gene Expression Omnibus. The classical t-test in Linear Models for Microarray Data package was used for DEM identification. TG prediction was performed using 5 databases. The regulatory network of the DEMs and their TGs was constructed using Cytoscape. Functional and pathway enrichment analysis was performed. The transcription factors (TFs), tumor-associated genes (TAG) and tumor suppressor genes (TSGs) were then identified. Three key DEMs hsa-miR-137, hsa-miR-520e, and hsa-miR-590-3p were identified. Hsa-miR-520e and hsa-miR-137 had 4 common TGs, including SNF related kinase, metal-regulatory transcription factor 1 (MTF1), round spermatid basic protein 1 and YTH N6-methyladenosine RNA binding protein 3; hsa-miR-590-3p and hsa-miR-137 had 14 common TGs, including NCK adaptor protein 1 (NCK1), EPH receptor A7, and stress-associated endoplasmic reticulum protein 1; hsa-miR-590-3p and hsa-miR-520e had 12 common TGs, including Krüppel-like factor (KLF) 13, twinfilin actin binding protein 1, and nuclear factor I B. Through the functional and pathway enrichments analysis, MTF1 was involved in regulation of gene expression and metabolic processes, and sequence-specific DNA binding TF activity. KLF13 was involved in regulation of gene expression and regulation of cellular metabolic processes. NCK1 was enriched in the axon guidance pathway. In addition, the functional and pathway enrichment analysis showed certain TGs, such as hypoxia-inducible factor 1α, AKT serine/threonine kinase 2, and rapamycin-insensitive companion of mammalian target of rapamycin, participated in the mTOR signaling pathway. The 3 key DEMs hsa-miR-137, hsa-miR-520e, and hsa-miR-590-3p may have important roles in the process of LS.

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Section: Discussionmentioning

confidence: 99%

Hsa-miR-137, hsa-miR-520e and hsa-miR-590-3p perform crucial roles in Lynch syndrome

Zhou

et al. 2016

Oncology Letters

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“…Preclinical studies have suggested a role for mTOR inhibitors in treatment of CRC, and this is being explored in phase I-II clinical trials with everolimus. A recent retrospective study suggested that the PI3K pathway could have a particularly high rate of derangement in hereditary nonpolyposis CRC (HNPCC), with 51 out of 58 (88%) of the analyzed tumors having alteration in at least one pathway component, raising the intriguing possibility of targeting this pathway in this small, but significant, subset of CRC (67). Finally, preclinical evidence suggests that the PI3K and MAPK pathways are strongly interlinked, and that the combination of MEK and PI3K inhibitors act synergistically to inhibit tumor cells with RAS mutations (68).…”

Section: On the Horizonmentioning

confidence: 99%

New Strategies in Colorectal Cancer: Biomarkers of Response to Epidermal Growth Factor Receptor Monoclonal Antibodies and Potential Therapeutic Targets in Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Pathways

Dasari

Messersmith

2010

Clinical Cancer Research

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Initial experience with the epidermal growth factor receptor monoclonal antibodies (EGFR MoAb) in unselected patients with metastatic colorectal cancer (mCRC) showed that most of the treated patients did not derive therapeutic benefit. This outcome has driven the search for biomarkers for this population. Recent advances have further shown the heterogeneous nature of this disease with multiple interlinked pathways being implicated. Two such pathways downstream to the EGFR, mitogen-activated protein kinase (MAPK) and (phosphoinositide 3-kinase) PI3K, have gained increasing attention and become targets for development of novel biomarkers and therapeutic agents. Here, we highlight recent progress.Clin Cancer Res; 16(15); 3811-8. ©2010 AACR.

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“…The PI3K/Akt/mTOR signaling axis is critical for proliferation, apoptosis resistance, angiogenesis, and metastasis and is central to the development and maintenance of CRC (16). Previous studies have reported the potential for the PI3K/Akt/mTOR network to be therapeutically targeted at multiple molecular levels (17,18). Activated PI3K generates a second messenger phosphatidylinositol(3-5)-triphosphate (PIP3); PIP3 then binds to and activates phosphoinositide-dependent kinase-1 (PDK1), which phosphorylates and activates Akt (19,20).…”

mentioning

confidence: 99%

Functional mechanism of the enhancement of 5-fluorouracil sensitivity by TUSC4 in colon cancer cells

Liu

Pei

et al. 2015

Oncology Letters

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Abstract. 5-Fluorouracil (5-FU) is the chemotherapeutic drug of choice for the treatment of metastatic colorectal cancer (CRC). Tumor suppressor candidate 4 (TUSC4), also referred to as nitrogen permease regulator-like 2 (NPRL2), is located at chromosome 3p21.3 and expressed in numerous normal tissues, including the heart, liver, skeletal muscle, kidney, and pancreas. The aim of the present study was to investigate the functional mechanism by which TUSC4 affects sensitivity to 5-FU and to determine its clinical significance in CRC. The results of the present study demonstrated that TUSC4 overexpression increases the sensitivity of HCT116 cells to 5-FU. The IC 50 of 5-FU was reduced in cells transduced with TUSC4 compared with negative control (NC) cells, and the effect of TUSC4 on 5-FU sensitivity was time dependent. Following TUSC4 transduction in HCT116 cells, a proportion of the cells were arrested in the G1 phase of the cell cycle, and a reduction in the S phase population was observed. Flow cytometry analysis revealed that TUSC4 transduction and 5-FU treatment increased apoptosis compared with NC cells. The mechanism through which TUSC4 overexpression enhances 5-FU sensitivity involves the downregulation of the function of the PI3K/Akt/mTOR network. Furthermore, 5-FU upregulated caspase-3 and caspase-9, promoting apoptosis in TUSC4-overexpressing cells compared with cells that were transduced with TUSC4 or treated with 5-FU and NC cells. The findings of the present study indicate that TUSC4 has potential as a biomarker for the prediction of the response to 5-FU and prognosis in patients with colorectal cancer and other types of human cancer. TUSC4 may also act as a molecular therapeutic agent for enhancing the patient's response to 5-FU treatment.

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Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

Cited by 51 publications

References 28 publications

Hsa-miR-137, hsa-miR-520e and hsa-miR-590-3p perform crucial roles in Lynch syndrome

Hsa-miR-137, hsa-miR-520e and hsa-miR-590-3p perform crucial roles in Lynch syndrome

New Strategies in Colorectal Cancer: Biomarkers of Response to Epidermal Growth Factor Receptor Monoclonal Antibodies and Potential Therapeutic Targets in Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Pathways

Functional mechanism of the enhancement of 5-fluorouracil sensitivity by TUSC4 in colon cancer cells

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