Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma

Milošević, Zorica; Pešić, Milica; Stanković, Tijana; Dinić, Jelena; Milovanović, Zorka; Stojšić, Jelena; Džodić, Radan; Tanić, Nikola; Banković, Jasna

doi:10.1016/j.trsl.2014.06.005

Cited by 44 publications

(32 citation statements)

References 54 publications

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“…Some research is currently underway to identify the signaling pathways and molecular mechanisms of metastasis in thyroid cancer (19)(20)(21)(22). In this study, we investigated the expression of ST6GalNAcII, via PI3K/Akt signaling pathway, to assess whether it effectively regulated the invasiveness of follicular thyroid carcinoma cell lines FTC-238 (lung metastasis) and FTC236 (lymph node metastasis) and FTC-133 (primary tumor).…”

Section: Discussionmentioning

confidence: 99%

ST6GalNAcII mediates tumor invasion through PI3K/Akt/NF-κB signaling pathway in follicular thyroid carcinoma

Miao

Zhao

2016

Oncology Reports

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Abstract. Altered sialylation, closely associated with tumor progression and metastasis, has been implicated in human thyroid carcinoma. The present study investigated the alteration in expression of ST6GalNAcII involved in invasion and to clarify the possible mechanism of ST6GalNAcII in the metastasis process in human follicular thyroid carcinoma cell lines. Using real-time PCR, western blot and IHC analysis, ST6GalNAcII differed in three follicular thyroid cancer cell lines (FTC133, primary and FTC238, lung metastasis). It also showed differential expression in follicular thyroid carcinoma and tissue specimens. In addition, we analyzed the PI3K/Akt signaling pathway. The altered expression of ST6GalNAcII corresponded to changed invasive phenotype of FTC-238 and FTC-133 cells in vitro and in vivo. Further studies showed that regulating ST6GalNAcII expression markedly modulated the activity of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Targeting the PI3K/Akt pathway by its specific inhibitor LY294002, or by Akt small interfering RNA (siRNA) resulted in reduced capacity in invasion of FTC-238. In conclusion, taken together, our results imply that ST6GalNAcII activated the invasion in follicular thyroid cancer cells through regulating the activity of PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

ST6GalNAcII mediates tumor invasion through PI3K/Akt/NF-κB signaling pathway in follicular thyroid carcinoma

Miao

Zhao

2016

Oncology Reports

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“…Primers and PCR conditions were previously described in Milosevic et al [22]. Sequences were determined with Applied Biosystems Incorporated (ABI) dye terminator sequencing kit according to the manufacturer's specifications on an ABI Prism 3130 automated sequencer (Applied Biosystems).…”

Section: Dna Sequencingmentioning

confidence: 99%

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

et al. 2015

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Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.

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“…Most data regarding the mechanisms of resistance have been derived from in vitro models of cells www.nature.com/aps Zhou Y et al Acta Pharmacologica Sinica npg selected by exposure to high drug concentrations. Given the up-regulation of the mTOR pathway in many chemoresistant cancer [2] , mTOR inhibitors provide a logical solution to re-sensitize tumor cells to chemotherapy or to delay the development of resistance to treatment. Recent studies have demonstrated the effectiveness of sirolimus (rapamycin) in solid tumors, such as metastatic breast [3] , pancreatic [4] , and renal carcinomas [5] .…”

Section: Introductionmentioning

confidence: 99%

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression

et al. 2016

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Aim: Multi-drug resistance poses a critical bottleneck in chemotherapy. given the up-regulation of mToR pathway in many chemoresistant cancers, we examined whether sirolimus (rapamycin), a first generation mTOR inhibitor, might induce human osteosarcoma (os) cell apoptosis and increase the sensitivity of os cells to anticancer drugs in vitro. Methods: human os cell line Mg63/aDM was treated with sirolimus alone or in combination with doxorubicin (aDM), gemcitabine (GEM) or methotrexate (MTX). Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. MiRnas in the cells were analyzed with miRna microarray. The targets of miR-34b were determined based on Targetscan analysis and luciferase reporter assays. The expression of relevant mRna and proteins was measured using qRT-PCR and Western blotting. MiR-34, PaK1 and aBCB1 levels in 40 tissue samples of os patients were analyzed using qRT-PCR and in situ hybridization assays. Results: Sirolimus (1−100 nmol/L) dose-dependently suppressed the cell proliferation (IC 50 =23.97 nmol/L) and induced apoptosis. Sirolimus (10 nmol/L) significantly sensitized the cells to anticancer drugs, leading to decreased IC 50 values of aDM, geM and MTX (from 25.48, 621.41 and 21.72 μmol/L to 4.93, 73.92 and 6.77 μmol/L, respectively). Treatment of with sirolimus increased miR-34b levels by a factor of 7.5 in the cells. upregulation of miR-34b also induced apoptosis and increased the sensitivity of the cells to the anticancer drugs, whereas transfection with miR-34b-aMo, an inhibitor of miR-34b, reversed the anti-proliferation effect of sirolimus. Two key regulators of cell cycle, apoptosis and multiple drug resistance, PaK1 and aBCB1, were demonstrated to be the direct targets of miR-34b. In 40 tissue samples of OS patients, significantly higher miR-34 ISH score and lower PAK5 and ABCB1 scores were detected in the chemo-sensitive group. Conclusion: sirolimus increases the sensitivity of human os cells to anticancer drugs in vitro by up-regulating miR-34b interacting with PaK1 and aBCB1. a low miR-34 level is an indicator of poor prognosis in os patients.

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Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma

Cited by 44 publications

References 54 publications

ST6GalNAcII mediates tumor invasion through PI3K/Akt/NF-κB signaling pathway in follicular thyroid carcinoma

ST6GalNAcII mediates tumor invasion through PI3K/Akt/NF-κB signaling pathway in follicular thyroid carcinoma

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression

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