Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

Xie, Xinyou; Liu, Huixing; Wang, Yanzhong; Zhou, Yi; Yu, Haitao; Li, Guiling; Ruan, Zhi; Li, Fengying; Wang, Xiuhong; Zhang, Jun

doi:10.18632/oncotarget.9962

Cited by 57 publications

(79 citation statements)

References 20 publications

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“…A previous study demonstrated that the phosphoinositide 3-kinase/protein kinase B signaling pathway exerts a critical function in the NNMT-mediated invasion of renal carcinoma cells (34). It has been revealed that NNMT increased the resistance to 5-fluorouracil partially through suppressing the signal-regulating kinase 1/p38 mitogen-activated protein kinase signaling pathway in colorectal cancer cells (17). Therefore, additional signaling pathways may be involved in the NNMT-mediated migration and invasion of gastric cancer cells and further studies are required to confirm these conclusions.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the serum levels of NNMT were significantly increased in patients with colorectal, lung and renal cell carcinoma compared with those in the control group (10,14,15). Previous studies have also demonstrated that the upregulation of NNMT is associated with poor prognosis, advanced tumor stage, tumor cell migration and invasion (9,16,17). Although, overexpression of NNMT has been identified in gastric cancer (18), the underlying molecular mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 97%

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Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

et al. 2018

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Abstract. Previous studies have demonstrated that nicotinamide N-methyltransferase (NNMT) is aberrantly expressed in a number of tumors. In the present study, it was demonstrated that the gene and protein levels of NNMT were significantly increased in gastric cancer cells. Furthermore, upregulation of NNMT significantly increased the expression of mesenchymal markers, including α-smooth muscle actin (SMA), vimentin and fibronectin, but decreased the levels of epithelial cadherin. Since transforming growth factor (TGF)-β1 may serve a key function in epithelial-mesenchymal transition (EMT), the effects of NNMT on the expression of TGF-β1 were investigated in BGC-823 cells. The results demonstrated that overexpression of NNMT significantly induced the expression of TGF-β1. However, knockdown of NNMT inhibited the expression of TGF-β1, mothers against decapentaplegic homolog (Smad)2 and α-SMA. Additionally, pre-incubation with TGF-β1 partially eliminated NNMT-mediated changes in EMT. Collectively, the results demonstrated that upregulation of NNMT in gastric cancer cells may increase the expression of TGF-β1, therefore activating TGF-β1/Smad signaling, which in turn promotes EMT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

et al. 2018

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“…NNMT mediates SAM depletion and attenuating histone methylation in various cells, including cancer cells, which resulted in the extensive gene expression changes in the tumor stroma. Besides, NNMT can promote the CRC cell growth and increase the resistance of CRC cells to 5‐fluorouracil through the 1‐MNA production . High expression of NNMT has been reported in multiple cancer types .…”

Section: Introductionmentioning

confidence: 99%

“…Besides, NNMT can promote the CRC cell growth and increase the resistance of CRC cells to 5-fluorouracil through the 1-MNA production. 5,6 High expression of NNMT has been reported in multiple cancer types. [7][8][9][10][11][12] Several studies have shown that the elevated NNMT level in cancer can be used for the early diagnosis and noninvasive diagnosis of some malignant tumors.…”

Section: Introductionmentioning

confidence: 99%

High stromal nicotinamide N‐methyltransferase (NNMT) indicates poor prognosis in colorectal cancer

Song

Miao

et al. 2020

Cancer Medicine

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Purpose Nicotinamide n‐methyltransferase (NNMT) has good biochemical activity and epigenetic regulation, and has been reported as a major metabolic regulator of cancer. The goal of this study was to investigate the significance of stromal NNMT expression in colorectal cancer (CRC). Patients and methods Stromal expression of NNMT in primary CRC, metastasis CRC, and their non‐cancerous tissues from 1088 CRC patients was examined by immunohistochemistry. The associations between stromal NNMT expression and survival outcomes in 967 patients with stage I‐III CRC were further evaluated with Kaplan‐Meier curve and Cox model analyses. Results NNMT expression was mainly sourced from stromal compartments and also elevated in CRC. Patients with high stromal NNMT (IHC‐score ≥ 106) have a worse survival than those patients with low stromal NNMT. In multiple Cox analyses, high expression of stromal NNMT remained as an independent risk factor in CRC for disease‐free survival with a hazard ratio (HR) of 1.415 (95% confidence interval [CI], 1.015‐1.972) and disease‐specific survival with a HR of 5.004 (95% CI, 2.301‐10.883). In addition, high stromal NNMT expression in CRC also indicates the poor survival outcomes in patients with early stage CRC (stage I and II) and in patients who undergo chemotherapy. Conclusion NNMT is mainly located in CRC stromal compartment. High stromal NNMT expression predicts an unfavorable postoperative prognosis.

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“…Although surgical resection has been the primary treatment modality, chemotherapy is still the important treatment for CRC 1. The chemotherapeutant, 5-fluorouracil (5-FU), causes cytotoxic damage by way of targeting the metabolism of RNA bases.…”

Section: Introductionmentioning

confidence: 99%

CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer

Yang¹,

Gao²,

Hu³

et al. 2016

OTT

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC.

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Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

Cited by 57 publications

References 20 publications

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression

High stromal nicotinamide N‐methyltransferase (NNMT) indicates poor prognosis in colorectal cancer

CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer

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