scholarly journals Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Se-Kyeong Jang ◽  
Sung-Eun Hong ◽  
Da-Hee Lee ◽  
Ji-Young Kim ◽  
Ji Yea Kim ◽  
...  
Keyword(s):  
Western Blot ◽  
Mtt Assay ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Metformin Treatment ◽  
Ampk Activation ◽  
Rt Pcr ◽  
Anticancer Effect ◽  
Cell Sensitivity ◽  
Therapeutic Value

Abstract Background Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. Methods To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. Results Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. Conclusions ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.

Inhibition of Migration and Invasion of Hepatocarcinoma HepG2 Cells by Dietary Saponins via Targeting HIF-1α

2018 ◽  
Vol 18 (7) ◽  
pp. 1025-1031
Author(s):  
Cheng Luo ◽  
Di Wu ◽  
Meiling Chen ◽  
Wenhua Miao ◽  
Changfeng Xue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Confocal Microscopy ◽  
Protein Expression ◽  
Mtt Assay ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Rt Pcr ◽  
Gene And Protein Expression ◽  
Simulated Hypoxia

Background: Different saponins from herbs have been used as tonic or functional foods, and for treatment of various diseases including cancers. Although clinical data has supported the function of these saponins, their underlying molecular mechanisms have not been well defined. Methods: With the simulated hypoxia created by 8 hours of Cu++ exposure and following 24 hour incubation with different concentration of saponins in HepG2 cells for MTT assay, migration and invasion assays, and for RT-PCR, and with each group of cells for immunofluorescence observation by confocal microscopy. Results： ZC-4 had the highest rate of inhibition of cell proliferation by MTT assay, and the highest inhibition of migration rate by in vitro scratch assay, while ZC-3 had the highest inhibition of invasion ratio by transwell assay. Under the same simulated hypoxia, the molecular mechanism of saponin function was conducted by measuring the gene expression of Hypoxia Inducible Factor (HIF)-1α through RT-PCR, in which ZC-3 showed a potent inhibition of gene HIF-1α. For the protein expression by immunofluorescence staining with confocal microscopy, HIF-1α was also inhibited by saponins, with the most potent one being ZC-4 after eight hours’ relatively hypoxia incubation. Conclusion: Saponins ZC-4 and ZC-3 have the potential to reduce HepG2 cell proliferation, migration and invasion caused by hypoxia through effectively inhibiting the gene and protein expression of HIF-1α directly and as antioxidant indirectly

scholarly journals Prodigiosin Alleviates Pulmonary Fibrosis Through Inhibiting miRNA-410 and TGF-β1/ADAMTS-1 Signaling Pathway

2018 ◽  
Vol 49 (2) ◽  
pp. 501-511 ◽  
Author(s):  
Hao Liu ◽  
Yi He ◽  
Zhaolei Jiang ◽  
Saie Shen ◽  
Ju Mei ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Western Blot ◽  
Lung Tissue ◽  
Mtt Assay ◽  
Model Group ◽  
Rt Pcr ◽  
Treatment Groups ◽  
Tgf Β1 ◽  
Masson Staining ◽  
Hydrocortisone Treatment

Background/Aims: Pulmonary fibrosis is a common outcome of various interstitial lung diseases. Prodigiosin (PG) is a series of red pigment with methoxypyrrole ring. This studyinvestigates therole of prodigiosin in pulmonary fibrosis and its underlying mechanisms. Methods: A pulmonary fibrosis rat model was established by intra-trachealinjection ofbleomycin A5. Rats were divided into 4 groups: Normal group, pulmonary fibrosis Model group, Prodigiosin treatment group and hydrocortisone treatmentgroup. HE and Masson staining were carried outto evaluate histopathological changes. The content of hydroxyproline in lung tissue was determined by alkaline hydrolysis. The expression of PICP and PIIINP was examined by ELISA. The mRNA expression of miR-410, TGF-β1 and ADAMTS1 in lung homogenate were detected by RT-PCR. The bronchoalveolar lavage fluid (BALF) and lung tissues of rats were collected and analyzed. Human embryonic pulmonary fibroblast (HEPF) was used for study in vitro. A dual-luciferase reporter assay was conducted to examine the effect of miR-410 on ADAMTS1 expression. Cell transfection was conducted to inhibit miR-410. MTT assay was performed to investigate cell proliferation. The expressions of miR-410, TGF-β1, ADAMTS1and other fibrosis related biomarkers (Col I, Col III, and α-SMA) wereexamined by RT-PCR and Western Blot. Results: HE and Masson staining showed thickened alveolar septum, hyperplasticcapillaries, and large areas of collagen fiber deposition in pulmonary fibrosis model rats. Rats in prodigiosin and hydrocortisone treatment groups had alleviated symptoms. There was high hydroxyproline expression in model rats, whereas the expression of hydroxyproline reduced after prodigiosin or hydrocortisone treatments. RT-PCR results showed high miR-410,high TGF-β1 and low ADAMTS1 in lung tissue of model rats. The expression of PICP and PIIINP werehigher in BALF of model group than in treatment groups. Prodigiosin and hydrocortisone treatment significantly reduced PICP and PIIINP content. RT-PCR and Western Blot analysis showed that prodigiosin inhibited expression of miR-410 and TGF-β1, but up-regulated ADAMTS1 expression. MTT assay indicated that prodigiosin inhibited HEPF proliferation induced by miR-410 overexpression. Conclusion: Prodigiosin down-regulates the expression of miR-410 and TGF-β1, up-regulates ADAMTS1, leading to decrease accumulation of fibrotic proteins. It could be used in alleviating pulmonary fibrosis.

scholarly journals TLR4 Signaling in MPP+-Induced Activation of BV-2 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Peng Zhou ◽  
Ruihui Weng ◽  
Zhaoyu Chen ◽  
Rui Wang ◽  
Jing Zou ◽  
...  
Keyword(s):  
Western Blot ◽  
Mtt Assay ◽  
Inflammatory Responses ◽  
Cell Model ◽  
Critical Role ◽  
Control Group ◽  
Immunofluorescence Technique ◽  
Rt Pcr ◽  
Sirna Interference

Aims.This work was conducted to establish anin vitroParkinson’s disease (PD) model by exposing BV-2 cells to 1-methyl-4-phenylpyridinium (MPP+) and exploring the roles of TLR2/TLR4/TLR9 in inflammatory responses to MPP+.Methods/Results.MTT assay showed that cell viability of BV-2 cells was 84.78 ± 0.86% and 81.18 ± 0.99% of the control after incubation with 0.1 mM MPP+for 12 hours and 24 hours, respectively. Viability was not significantly different from the control group. With immunofluorescence technique, we found that MPP+incubation at 0.1 mM for 12 hours was the best condition to activate BV-2 cells. In this condition, the levels of TNF-α, IL-1β, and iNOS protein were statistically increased compared to the control according to ELISA tests. Real time RT-PCR and western blot measurements showed thatTLR4was statistically increased after 0.1 mM MPP+incubation for 12 hours. Furthermore, after siRNA interference ofTLR4mRNA, NF-κB activation and the levels of TNF-α, IL-1β, and iNOS were all statistically decreased in this cell model.Conclusion.MPP+incubation at the concentration of 0.1 mM for 12 hours is the best condition to activate BV-2 cells for mimicking PD inflammation in BV-2 cells. TLR4 signalling plays a critical role in the activation of BV-2 cells and the induction of inflammation in this cell model.

scholarly journals High Glucose Enhances the Odonto/Osteogenic Differentiation of Stem Cells from Apical Papilla via NF-KappaB Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Yanping Wang ◽  
Yanqiu Wang ◽  
Yadie Lu ◽  
Jinhua Yu
Keyword(s):  
Stem Cells ◽  
Western Blot ◽  
Osteogenic Differentiation ◽  
Real Time ◽  
Signaling Pathway ◽  
Mtt Assay ◽  
High Glucose ◽  
Rt Pcr ◽  
Alizarin Red ◽  
Apical Papilla

Objective. The transport and metabolism of glucose are important during mammalian development. High glucose can mediate the biological characteristics of mesenchymal stem cells (MSCs). However, the role of high glucose in the odonto/osteogenic differentiation of stem cells from apical papilla (SCAPs) is unclear. Materials and Methods. SCAPs were isolated and identified in vitro. Then, SCAPs were cultured in normal α-MEM and high glucose α-MEM separately. MTT assay was applied to observe the proliferation of SCAPs. ALP activity, alizarin red staining, real-time RT-PCR, and western blot were used to detect the odonto/osteogenic capacity of SCAPs as well as the participation of NF-κB pathway. Results. SCAPs in 25mmol/L glucose group expressed the maximum proteins of RUNX2 and ALP as compared with those in 5, 10, and 15 mmol/L groups. MTT assay showed that 25 mmol/L glucose suppressed the proliferation of SCAPs. ALP assay, alizarin red staining, real-time RT-PCR, and western blot showed 25 mmol/L high glucose can obviously enhance the odonto/osteogenic capacity of SCAPs. Moreover, the NF-κB pathway was activated in 25mmol/L glucose-treated SCAPs and the odonto/osteogenic differentiation was inhibited following the inhibition of NF-κB signaling pathway. Conclusions. High glucose can enhance the odonto/osteogenic capacity of SCAPs via NF-κB pathway.

scholarly journals Protective Effects of Baicalin on Peritoneal Tight Junctions in Piglets Challenged with Glaesserella parasuis

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1268
Author(s):  
Jiacheng Zhang ◽  
Zhaoran Zhang ◽  
Jianfeng Xu ◽  
Chun Ye ◽  
Shulin Fu ◽  
...  
Keyword(s):  
Western Blot ◽  
Protective Effect ◽  
Tight Junctions ◽  
Molecular Mechanisms ◽  
Distribution Patterns ◽  
Protective Effects ◽  
Rt Pcr ◽  
Protective Mechanisms ◽  
Prevention And Treatment ◽  
Natural Agent

Glaesserella parasuis (G. parasuis) causes inflammation and damage to piglets. Whether polyserositis caused by G. parasuis is due to tight junctions damage and the protective effect of baicalin on it have not been examined. Therefore, this study aims to investigate the effects of baicalin on peritoneal tight junctions of piglets challenged with G. parasuis and its underlying molecular mechanisms. Piglets were challenged with G. parasuis and treated with or without baicalin. RT-PCR was performed to examine the expression of peritoneal tight junctions genes. Immunofluorescence was carried out to detect the distribution patterns of tight junctions proteins. Western blot assays were carried out to determine the involved signaling pathways. Our data showed that G. parasuis infection can down-regulate the tight junctions expression and disrupt the distribution of tight junctions proteins. Baicalin can alleviate the down-regulation of tight junctions mRNA in peritoneum, prevent the abnormalities and maintain the continuous organization of tight junctions. Our results provide novel evidence to support that baicalin has the capacity to protect peritoneal tight junctions from G. parasuis-induced inflammation. The protective mechanisms of baicalin could be associated with inhibition of the activation of PKC and MLCK/MLC signaling pathway. Taken together, these data demonstrated that baicalin is a promising natural agent for the prevention and treatment of G. parasuis infection.

scholarly journals Nuclear Magnetic Resonance-Based Metabolomic Analysis of the Anticancer Effect of Metformin Treatment on Cholangiocarcinoma Cells

2020 ◽  
Vol 10 ◽  
Author(s):  
Jin Zhang ◽  
Caihua Hang ◽  
Ting Jiang ◽  
Shenghui Yi ◽  
Wei Shao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Umbilical Vein ◽  
Cancer Therapies ◽  
Metformin Treatment ◽  
Anticancer Effect ◽  
Multivariate Statistical ◽  
Cycle Arrest ◽  
Diabetes Drug ◽  
Umbilical Vein Endothelial Cells ◽  
And Control

Metformin is a widely prescribed anti-diabetes drug with potential utilities for cancer therapies. Several studies have related metformin to the reduced risk of cholangiocarcinoma (CCA), highlighting its potentialities for the treatments of CCA. However, the underlying molecular mechanisms remain elusive. Here, we demonstrated that metformin treatment could inhibit proliferations of the human CCA cell lines Mz-ChA-1 and QBC939 in dose-dependent manners. The NMR-based metabonomic analyses showed distinct discriminations between the metformin-treated (Met) and control (Ctrl) groups of both CCA cells. Characteristic metabolites were identified by a combination of multivariate statistical analysis of 1D 1H-NMR spectral data and the pair-wise t-test of metabolite levels. We then identified four significantly altered metabolic pathways based on the characteristic metabolites, including glucose metabolism, oxidative stress-related metabolism, energy metabolism, and amino acids metabolism. Comparing CCA cells with normal human umbilical vein endothelial cells (HUVECs), we found that metformin treatment profoundly promoted glycolysis and specifically increased the levels of BCAAs and UDP-GlcNAc, implying the occurrence of autophagy and cell cycle arrest in metformin-treated CAA cells. This work provides a mechanistic understanding of the anticancer effect of metformin treatment on CAA cells, and is beneficial to further developments of metformin as an anticancer drug.

scholarly journals YTHDC2 Promotes the Apoptosis of Colorectal Cancer Cells Through the p38MAPK Signaling Pathway

2020 ◽  
Author(s):  
Tao Yu ◽  
YanYan Xu ◽  
Tao Sun ◽  
Di Huang ◽  
Feng Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Flow Cytometry ◽  
Western Blot ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Gene Set Enrichment Analysis ◽  
Rt Pcr ◽  
P38mapk Signaling

Abstract Background The role of the m6A-binding protein YTHDC2 in the occurrence and development of colorectal cancer (CRC) is unclear. We aimed to explore the molecular mechanisms underlying this process and clarify the signaling pathway involved. Methods Firstly, the relationship between YTHDC2 and CRC in TCGA database was analyzed to identify relevant signaling pathways and biological processes. Then, western blot was used to analyze expression of YTHDC2 in HCT116 and Caco2 cells. After knockdown or overexpression of YTHDC2 in the above cells, RT-PCR and western blot were used to analyze p38MAPK, p-p38MAPK, and downstream apoptosis-related proteins in the MAPK signaling pathway. Flow cytometry was performed to detect changes in apoptosis. Results And the results were shown that the expression of YTHDC2 was significantly lower in tumor tissues than in normal tissues. Increased expression of YTHDC2 was associated with better overall survival among patients with CRC. Gene set enrichment analysis revealed that YTHDC2 regulates the MAPK signaling pathway. Flow cytometry revealed apoptosis was significantly reduced and enhanced in response to YTHDC2 knockdown and overexpression, respectively. There was no significant change in the expression of p38MAPK, while p-p38MAPK was significantly increased in response to overexpression and decreased in response to knockdown. Gene Expression Profiling Interactive Analysis showed apoptotic protein expression to be positively correlated with YTHDC2 expression, consistent with the results of RT-PCR and western blot. Conclusion In general, apoptosis of CRC cells is promoted by YTHDC2 via activation of the exogenous death receptor and endogenous mitochondrial apoptosis-related pathways in the p38MAPK signaling pathway.

scholarly journals Potentsial'nye vozmozhnosti metformina v profilaktike i lechenii onkologicheskikh zabolevaniy u bol'nykh sakharnym diabetom 2 tipa

2011 ◽  
Vol 8 (1) ◽  
pp. 40-49
Author(s):  
I I Dedov ◽  
S A Butrova ◽  
M A Berkovskaya
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Amp Kinase ◽  
Anticancer Effect ◽  
Breast And Ovarian Cancer ◽  
Increase Insulin Sensitivity ◽  
Molecular Features ◽  
Increased Risk ◽  
Stimulation Of

Diabetes mellitus is associated with increased risk of several types of cancer, and also with increased cancer mortality. Chronic hyperinsulinemia plays the main pathogenetic role in this association, which is mediated by a number of molecular mechanisms, described in this issue. Drugs that increase insulin sensitivity and reduce hyperinsulinemia (metformin in the first place) display anticancer effect. Aside from the anticancer effect, mediated by reduction of insulin resistance, metformin may directly suppress cancer cells growth and proliferation via stimulation of AMP kinase (AMPK). Antiproliferative action of metformin in breast and ovarian cancer is confirmed in a number of experimental and clinical trials. Its found out that therapeutic effect of metformin in treatment of breast cancer depends on the presence/absence of some molecular features of the tumor (for example, increased expression of HER2 and/or activation of p70S6K1). In order to specify mechanisms of action and effects of metformin in oncological practice several trials are being conducted or planned, most of all, in all subtypes of breast cancer. Confirmation of the anticancer effectiveness of metformin will promote an expansion of its use in clinical practice and in clinical oncology, particularly.

scholarly journals miR-17-5p Combined with Epirubicin Inhibits the Progression of Breast Cancer Cells

2020 ◽  
Author(s):  
Lingling Zhao ◽  
Zhongjian Zhu ◽  
Jiang Du ◽  
Yuanyu Zhao ◽  
Dandan Fan
Keyword(s):  
Breast Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Mtt Assay ◽  
Breast Cancer Cells ◽  
Luciferase Reporter ◽  
Rt Pcr ◽  
Expression Levels ◽  
Cancer Tissues ◽  
Mcf 7

Abstract Background: Breast cancer is the most common malignant tumor for women, which has been ranked first in women’ s cancer-related death. The objectives of the study are to uncover the underlying mechanisms of combination therapy of epirubicin with miR-17-5p in breast cancer. Methods: The expression levels of miR-17-5p were determined by quantitative RT-PCR. The survival rate of MCF-7 cell was detected respectively by MTT assay. The expression levels of miR-17-5p in MCF-7 cell was tested respectively with Ep via quantitative RT-PCR. miR-17-5p was to be transected with miR-17-5p mimic and negative control of miR-17-5p mimic (NC). Quantitative RT-PCR, MTT assay, flow cytometry assay, western blot for the proliferation and apoptosis related proteins were performed to determine the function of miR-17-5p in breast cancer cells. The bioinformatic programs TargetScan was used to predict the targets for miR-17-5p. Luciferase reporter gene assay system was used to validate and determine the targets of miR-17-5p. The relation between targets protein levels in breast cancer cells was investigated by western blot. Results: The expression levels of miR-17-5p was associated with the breast cancer tissues. The levels of miR-17-5p was down-regulated in breast cancer tissues and cells. Ep could inhibit viability of cancer cells in a concentration dependent manner and promote the expression of miR-17-5p in breast cancer cell lines. Over-expression of miR-17-5p induced cell apoptosis and upregulated the expression of p53, p21 and p27. miR-17-5p co-cultured with Ep is better than the other groups. The relative luciferase activity revealed that STAT3 was a potential target gene of miR-17-5p. Conclusions: Our work will prove that epirubicin regulated the expression of miR-17-5p to strengthen this effect of epirubicin and inhibited the progression of breast cancer.

MEK 1/2 Inhibitor U0126 Reversed Imatinib Resistance in IM-Resistant K562R

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4914-4914
Author(s):  
Yuping Gong ◽  
Juan Lin ◽  
Ting Niu
Keyword(s):  
Western Blot ◽  
Cell Line ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mtt Assay ◽  
K562 Cell ◽  
Single Agent ◽  
Rt Pcr ◽  
Imatinib Resistance ◽  
Ic50 Values

Abstract Abstract 4914 Objective To study the anti-leukemic activity of MEK inhibitor U0126 alone or in combination with imatinib and explored the reversing mechanism to imatinib resistance in imatinib resistant K562R cell line. Methods Cytotoxicity of drug was detected by the MTT assay in the IM-sensitive cell line K562 and IM-resistant cell line K562R. Western Blot assay were employed to examine the expression of p-cAbl, p-Lyn, p-STAT5, ERK signaling pathway (p-cRaf, p-MEK, p-ERK), PI3K/AKT/mTOR signaling pathway(p-AKT, p-mTOR, p-4EBP1) and the apoptosis related proteins (Bax, Bcl2). The apoptosis rates were analyzed by Annexin V/PI double staining flow cytometry assay. The levels of lyn and erk1/2 gene were assayed by RT-PCR. Results 1. BCR-ABL-independent activation of Lyn and ERK1/2 may be the IM resistant mechanism in K562R cell line. The IC50 value of K562R cell line(1. 505±0. 459 μmol/L) inhibited by imatinib for 72 hours was higher than the values of K562(0. 159±0. 032μmol/L) and the Resistant Fold(RF)was 9. 465. Western Blot assays showed that p-Lyn, p-MEK and p-ERK of ERK pathway, p-mTOR and p-4EPB1 were over-expressed in K562R cell line relative to K562 cell line. However, the levels of p-cAbl, p-STAT5, p-Raf, p-AKT of PI3K/AKT/mTOR were similar in the K562R and K562 cell lines. The treatment of IM could reduce the expression of p-cAbl and p-MEK, but not that of p-Lyn, p-ERK, p-mTOR, p-4EBP1, and even up-regulate the p-Lyn, p-ERK, p-mTOR. The expression of Bax, Bcl2 and the apoptosis rates were the similar in both cell lines. 2. MEK1/2 inhibitor U0126 could reverse the IM resistance in K562R cell line. MTT assay showed single-agent U0126 is more sensitive to K562R than K562. The IC50 values of the two cell lines were 34. 235±5. 658 μmol/L and 85. 824±4. 474 μmol/L respectively. The combination of imatinib and U0126 markedly enhanced inhibitory effect as measured by MTT assay in K562R cell line, combination with 10μmol/L U0126, the IC50 values of IM was 0. 134±0. 059μmol/L, which reduced to 8. 9% of single IM treatment. 3. The reversing mechanism of U0126 to imatinib resistance in K562R cell line. Western Blot showed single IM up-regulated the p-Lyn and p-ERK, while U0126 reduced the expression of them, the combination of the IM and U0126 could synergisticly reduce the p-Lyn expression and neutralize the up-regulation of p-ERK caused by IM single agent. Single IM also up-regulated the p-mTOR in K562R while U0126 reduced it, single IM or U0126 had no influence on p-4EBP1 in K562R, the combination of the two drugs could synergisticly reduce the p-4EBP1 and neutralize the up-regulation of p-mTOR caused by IM single agent. IM but not U0126could reduce p-cAbl and the combination of the two was more effective than IM treatment. IM alone or combination with U0126 could not regulate p-STAT5 expression in K562R. RT-PCR showed that neither IM treatment nor its combination with U0126 could change the level of lyn and erk1, 2 gene in the cell lines. Conclusions 1. BCR-ABL-independent activation of Lyn and ERK1/2 involved in IM resistance mechanism in IM-resistant K562R cell line. Imatinib alone could up-regulated the expression of the p-Lyn, p-ERK, p-mTOR in K562R cell line. MEK1/2 inhibitor U0126 could reverse the IM resistance by reducing the expression of the p-Lyn, p-ERK, p-mTOR, p-4EBP1 of IM-resistant K562R cell line, and the combination of U0216 and Imatinib could synergisticly depress up-regulation of the p-Lyn, p-ERK, p-mTOR and p-4EBP1 caused by IM. Grant support: National Natural Science Foundation of China (No. 30770912), Foundation of the Science & Technology Department of Sichuan Province (No. 2008SZ0017). Disclosures: No relevant conflicts of interest to declare.

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