Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells

Yu, Haitao; Zhou, Xi; Wang, Yanzhong; Huang, Xucheng; Yang, Jun; Zeng, Jin; Li, Guoli; Xie, Xinyou; Zhang, Jun

doi:10.1186/s12935-020-01279-8

Cited by 21 publications

(14 citation statements)

References 33 publications

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“…We previously reported that NNMT could promote cell proliferation, reduce reactive oxygen species (ROS), accelerate cell cycle, inhibit cell apoptosis, and enhance resistance to 5-FU in human CRC cells [6,7]. We also demonstrated that NNMT could promote cell growth, inhibit apoptosis, inhibit autophagy, and enhance chemoresistance in breast cancer [8][9][10]. These data support Biomolecules 2021, 11, 1295 2 of 19 the notion that NNMT is an attractive tumor marker and therapeutic target.…”

Section: Introductionsupporting

confidence: 60%

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Fang

Shao

et al. 2021

Biomolecules

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Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of 5-FU. The aim of the present study is to explore the effect of Cur on attenuating NNMT-induced resistance to 5-FU in CRC. A panel of CRC cell lines with different NNMT expressions are used to characterize the effect of Cur. Herein, it is observed that Cur can depress the expression of NNMT and p-STAT3 in CRC cells. Furthermore, Cur can induce inhibition of cell proliferation, G2/M phase cell cycle arrest, and reactive oxygen species (ROS) generation, especially in high-NNMT-expression CRC cell lines. Cur can also re-sensitize high-NNMT-expression CRC cells to 5-FU both in vitro and in vivo. In summary, it is proposed that Cur can reverse NNMT-induced cell proliferation and 5-FU resistance through ROS generation and cell cycle arrest. Given that Cur has long been used, we suppose that Cur is a promising anticancer drug candidate with minimal side effects for human CRC therapy and can attenuate NNMT-induced resistance to 5-FU.

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Section: Introductionsupporting

confidence: 60%

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Fang

Shao

et al. 2021

Biomolecules

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“…This thrombolytic response was independent of changes in arterial blood pressure; instead, the effects of MNA were mediated via an increase in cyclooxygenase-2 (COX-2)-mediated release of prostacyclin (PGI 2 ). MNA reduced apoptosis of SH-SY5Y human neuroblastoma cells in a dose-dependent manner [37], in addition to replicating many of the effects of NNMT expression upon tumour-promoting biochemical changes such as increased ATP synthesis and CxI activity, plus changes in cell morphology [37,108], all cognisant with changes observed during metastasis in cancers such as colorectal carcinoma [146][147][148] and breast cancer [149]. Elevated MNA levels correlate with lower survival rate and shorter life expectancy of patients with cervical cancer and thus most likely contributes to the disease progression [150].…”

Section: Synthesis Of 1-methylnicotinamidementioning

confidence: 99%

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons

Facey

2021

Biomolecules

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Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.

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“…Mthfd2 expression was upregulated in the Trsp f/f -Ucp1-Cre +/- mice, and further enhanced after acute cold exposure ( Figure 9 a). On the other hand, Nnmt, which encodes nicotinamide N-methyl transferase, is an enzyme that inhibits autophagy in breast cancer cells [ 43 ]. It showed a dramatic ~24-fold upregulation in BAT of Trsp f/f -Ucp1-Cre +/− mice after cold exposure compared to corresponding controls ( Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Adaptive Thermogenesis in a Mouse Model Lacking Selenoprotein Biosynthesis in Brown Adipocytes

Seale

Ogawa-Wong

Watanabe

et al. 2021

IJMS

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Selenoproteins are a class of proteins with the selenium-containing amino acid selenocysteine (Sec) in their primary structure. Sec is incorporated into selenoproteins via recoding of the stop codon UGA, with specific cis and trans factors required during translation to avoid UGA recognition as a stop codon, including a Sec-specific tRNA, tRNA[Ser]Sec, encoded in mice by the gene Trsp. Whole-body deletion of Trsp in mouse is embryonically lethal, while targeted deletion of Trsp in mice has been used to understand the role of selenoproteins in the health and physiology of various tissues. We developed a mouse model with the targeted deletion of Trsp in brown adipocytes (Trspf/f-Ucp1-Cre+/−), a cell type predominant in brown adipose tissue (BAT) controlling energy expenditure via activation of adaptive thermogenesis, mostly using uncoupling protein 1 (Ucp1). At room temperature, Trspf/f-Ucp1-Cre+/− mice maintain oxygen consumption and Ucp1 expression, with male Trspf/f-Ucp1-Cre+/− mice accumulating more triglycerides in BAT than both female Trspf/f-Ucp1-Cre+/− mice or Trspf/f controls. Acute cold exposure neither reduced core body temperature nor changed the expression of selenoprotein iodothyronine deiodinase type II (Dio2), a marker of adaptive thermogenesis, in Trspf/f-Ucp1-Cre+/− mice. Microarray analysis of BAT from Trspf/f-Ucp1-Cre+/− mice revealed glutathione S-transferase alpha 3 (Gsta3) and ELMO domain containing 2 (Elmod2) as the transcripts most affected by the loss of Trsp. Male Trspf/f-Ucp1-Cre+/− mice showed mild hypothyroidism while downregulating thyroid hormone-responsive genes Thrsp and Tshr in their BATs. In summary, modest changes in the BAT of Trspf/f-Ucp1-Cre +/− mice implicate a mild thyroid hormone dysfunction in brown adipocytes.

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Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells

Cited by 21 publications

References 33 publications

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Adaptive Thermogenesis in a Mouse Model Lacking Selenoprotein Biosynthesis in Brown Adipocytes

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