Hyperglycemia Regulates TXNIP/TRX/ROS Axis via p38 MAPK and ERK Pathways in Pancreatic Cancer

Li, Wei; Wu, Zheng; Ma, Qingyong; Liu, Jiangbo; Xu, Qinhong; Han, Liang; Duan, Wanxing; Lv, Yunfu; Wang, Fengfei; Reindl, Katie M.; Wu, Erxi

doi:10.2174/1568009614666140331231658

Cited by 29 publications

(31 citation statements)

References 21 publications

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“…Deprivation of glucose induced supra-physiological levels of phospho-tyrosine signaling and a modest increase in phosphorylation of AMPK, AKT, and p42/44 in breast, kidney, lung, colon, prostate and ovarian cancer cells [21, 34–36]. On the other hand, it has recently been reported that high glucose stimulated phosphorylation of AKT, reduced AMPK phosphorylation and activated MAPK pathways in cancer cells [37–40]. These studies suggest these signaling pathways have switch-like properties that produce differential kinetics under different metabolic stresses.…”

Section: Discussionmentioning

confidence: 99%

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Han

Zhang

Guo

et al. 2015

Gynecologic Oncology

146

109

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Objectives Obesity and diabetes are well-known risk factors for the development of endometrial cancer. A high rate of aerobic glycolysis represents a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. This study aimed to investigate the effect of various concentrations of glucose on cell proliferation in endometrial cancer. Methods ECC-1 and Ishikawa cells were treated with low glucose (1mM), normal glucose (5mM) and high glucose (25mM), and cytotoxicity, apoptosis, cell cycle, adhesion/invasion, and changes of AMPK/mTOR/S6 and MAPK pathways were evaluated. Results Our results revealed that high glucose increased cell growth and clonogenicity in two endometrial cancer cell lines in a dose dependent manner. Low glucose induced the activity of cleaved caspase 3 and caused cell cycle G1 arrest. High glucose increased the ability of adhesion and invasion by decreasing E-Cadherin and increasing Snail expression. In addition, high glucose increased glucose uptake and glycolytic activity through modulating the AMPK/mTOR/S6 and MAPK pathways. Conclusions Our findings suggest that glucose stimulated cell proliferation through multiple complex signaling pathways. Targeting glucose metabolism may be a promising therapeutic strategy in the treatment of endometrial cancer.

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Section: Discussionmentioning

confidence: 99%

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Han

Zhang

Guo

et al. 2015

Gynecologic Oncology

146

109

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“…Furthermore, Tyagi et al (8) indicated that P-21 activated kinase 4 promotes the proliferation and survival of pancreatic cancer cells via the ERK pathway. In addition, Li et al (9) reported that hyperglycemia regulates the thioredoxin-interacting protein/ thioredoxin/reactive oxygen species axis of pancreatic cancer via the p38 MAPK and ERK pathways. Zheng et al (10) reported that gemcitabine inhibited tumour growth and promoted apoptosis of pancreatic cancer via upregulation of pERK1/2 levels.…”

Section: Introductionmentioning

confidence: 99%

Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling

et al. 2016

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Abstract. Paeoniflorin exhibits anticancer, anti-inflammatory and antioxidation effects, as well as specific pharmacological effects on smooth muscle and the immune, cardiovascular and central nervous systems. The present study aimed to investigate the anticancer effects of paeoniflorin on pancreatic cancer cells and to elucidate the mechanisms by which these effects occur. In the present study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were performed to assess cell viability and cell cytotoxicity of BXPC-3 human pancreatic cancer cells, respectively. Cellular apoptosis and caspase-3/9 activities were analyzed using an Annexin V-fluorescein isothiocyanate/propidium iodide Apoptosis Detection kit, a DAPI staining assay and colorimetric kits, respectively. Matrix metalloproteinase-9 (MMP-9) and extracellular signal-regulated kinases (ERK) protein expression in BXPC-3 cells were also investigated using gelatin zymography assays and western blot analysis, respectively. In the present study, paeoniflorin was found to inhibit the cell viability and increase cell cytotoxicity of BXPC-3 cells in a dose-and time-dependent manner. In addition, cellular apoptosis, as well as caspase-3 and -9 activity of BXPC-3 cells was increased following paeoniflorin treatment. Notably, paeoniflorin reduced MMP-9 and ERK protein expression in BXPC-3 cells. These results indicate that paeoniflorin exhibits a potential anticancer effect by enhancing human pancreatic cancer cell apoptosis via the suppression of MMP-9 and ERK signaling.

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“…Previous studies have indicated that ROS induced TXNIP may impair the ability of cells to remove intracellular ROS (23,50,51), while increased intracellular ROS may contribute to the metastatic process of HBV-associated HCC (23,24,52). Whether TXNIP is involved in HBx-induced metastasis of HBV-associated HCC is worthy of further study.…”

Section: Discussionmentioning

confidence: 96%

“…HBx is involved in metastasis of HBV-associated HCC by various means, including upregulating intracellular ROS levels (23,24). Acting as a key mediatory factor of intracellular ROS level, TXNIP is involved in the progression of numerous types of tumor (26).…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, mechanisms of HCC metastasis promotion by HBx include: Promotion of epithelial-mesenchymal transition (EMT) (12,13); degradation of the extracellular matrix (ECM) (14,15); reduction of cell-ECM interactions (16); alteration of the cellular morphology conductive to migration and motility (17,18); repression of miRNA-148a (19) or upregulation of miRNA-143 (20). HBx may also upregulate intracellular ROS levels (21,22), and ROS have been demonstrated to regulate the expression of EMT and metastasis-associated genes, including E-cadherin, integrin and matrix metalloproteinases in HCC cells, which contribute to HCC metastasis (23,24). Thioredoxin interacting protein (TXNIP), also known as vitamin D3 upregulated protein 1, is involved in a wide range of cellular processes, including proliferation, apoptosis, lipid and glucose metabolism and redox regulation (25).…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein promotes hepatocellular carcinoma invasion and metastasis via upregulating thioredoxin interacting protein

Nong

et al. 2017

Oncology Letters

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Abstract. Hepatitis B virus X protein (HBx), a multifunctional protein encoded by the X gene of the hepatitis B virus (HBV) is involved in the metastasis of HBV-associated hepatocellular carcinoma (HCC) through various pathways, including upregulating intracellular reactive oxygen species (ROS). Thioredoxin interacting protein (TXNIP) is a key mediator of intracellular ROS, but its function in HBx-mediated metastasis of HBV-associated HCC is elusive. In the present study, HBV-associated HCC tissues with or without metastasis and HepG2 cells were used to study the function of TXNIP in HBx-mediated metastasis of HBV-associated HCC. Initially, the expression levels of TXNIP and HBx in HBV-associated HCC tissues were detected by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. The results revealed that high expression of TXNIP may be an independent risk factor for metastasis of HBV-associated HCC, and the mRNA levels of TXNIP and HBx were positively associated. Secondly, the association between HBx and TXNIP was investigated using a HBx expression stable cell line, in which HBx expression was induced and controlled by doxycycline. The results demonstrated that HBx may upregulate TXNIP expression in HepG2 cells. Thirdly, the effects of TXNIP and HBx on HepG2 cell migration and invasion were studied by scratch and Matrigel invasion assays, respectively. The results demonstrated that TXNIP overexpression enhanced HepG2 cell migration and invasion. In addition, ectopic expression of HBx promoted HepG2 cell migration and invasion, and this effect may be attenuated by knockdown of TXNIP expression, which indicated that TXNIP may be involved in the process. In summary, the present results demonstrated that TXNIP may be involved in HBx-mediated metastasis of HBV-associated HCC.

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Hyperglycemia Regulates TXNIP/TRX/ROS Axis via p38 MAPK and ERK Pathways in Pancreatic Cancer

Cited by 29 publications

References 21 publications

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Paeoniflorin inhibits human pancreatic cancer cell apoptosis via suppression of MMP-9 and ERK signaling

Hepatitis B virus X protein promotes hepatocellular carcinoma invasion and metastasis via upregulating thioredoxin interacting protein

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