The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD

Fu, Chengzhang; Sikandar, Asfandyar; Donner, Jannik; Zaburannyi, Nestor; Herrmann, Jennifer; Reck, Michael; Wagner‐Döbler, Irene; Koehnke, Jesko; Müller, Rolf

doi:10.1038/s41467-017-01671-5

Cited by 73 publications

(74 citation statements)

References 47 publications

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“…24 KRAS mutation status is associated with the expression of MTHFD2 in lung cancer. [14][15][16]21,24 In future studies, it may also be informative to development of selective MTHFD2 inhibitors testing their effects in preclinical trials and the combinatorial effects with clinical chemotherapy drugs. 26 Previously published studies have relied on shRNA or small molecule inhibitors directed suppression of MTHFD2.…”

Section: Discussionmentioning

confidence: 99%

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Down‐regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle‐related genes

Chang

Yang

Cai

et al. 2019

J Cellular Molecular Medi

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Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. It has been reported to be overexpressed in several malignancies. However, the relationship between the expression of MTHFD2 and non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that MTHFD2 was significantly overexpressed in NSCLC tissues and cell lines. Knockdown of MTHFD2 resulted in reduced cell growth and tumorigenicity in vitro and in vivo. Besides, the mRNA and protein expression level of cell cycle genes, such as CCNA2, MCM7 and SKP2, was decreased in MTHFD2 knockdown H1299 cells. Our results indicate that the inhibitory effect of MTHFD2 knockdown on NSCLC may be mediated via suppressing cell cycle-related genes. These findings delineate the role of MTHFD2 in the development of NSCLC and may have potential applications in the treatment of NSCLC. K E Y W O R D S bioinformatics, cell cycle, methylenetetrahydrofolate dehydrogenase 2, non-small cell lung cancer | 1569 YU et al. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Yu C, Yang L, Cai M, et al. Downregulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes. J Cell Mol Med.

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Section: Discussionmentioning

confidence: 99%

“…12,13 More recently, studies showed that MTHFD2 could confer redox homeostasis and promote caners cell growth, metastasis and correlate with poor survival. 15,16 To date, the relation- 15,16 To date, the relation- …”

Section: Introductionmentioning

confidence: 99%

Down‐regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle‐related genes

Chang

Yang

Cai

et al. 2019

J Cellular Molecular Medi

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“…If we exclude technical issues such as inactivation during incorporation into the composite material, the lack of activity may reflect the biodegradation of carolacton, its sequestration by matrix components or resistance against its mechanism of action. Carolacton was recently shown to specifically inhibit the essential folate-dependent enzyme FolD/MTHFD, which is present in all bacteria [26]. However, in direct tests, carolacton has only been shown to inhibit certain isolates of S. pneumoniae [27] and does not affect the growth of most bacteria, including S. mutans at neutral or higher pH [10].…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing of biofilm microbiomes on dental composite materials

Conrads

Wendt

Hetrodt

et al. 2019

Journal of Oral Microbiology

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Background: The microbiome on dental composites has not been studied in detail before. It has not been conclusively clarified whether restorative materials influence the oral microbiome. Methods: We used Illumina Miseq next-generation sequencing of the 16S V1-V2 region to compare the colonisation patterns of bovine enamel (BE) and the composite materials Grandio Flow (GF) and Grandio Blocs (GB) after 48 h in vivo in 14 volunteers. Applying a new method to maintain the oral microbiome ex vivo for 48 h also, we compared the microbiome on GF alone and with the new antimicrobial substance carolacton (GF+C). Results: All in vitro biofilm communities showed a higher diversity and richness than those grown in vivo but the very different atmospheric conditions must be considered. Contrary to expectations, there were only a few significant differences between BE and the composite materials GB and GF either in vivo or in vitro: Oribacterium, Peptostreptococcaceae [XI][G-1] and Streptococcus mutans were more prevalent and Megasphaera, Prevotella oulorum, Veillonella atypica, V. parvula, Gemella morbillorum, and Fusobacterium periodonticum were less prevalent on BE than on composites. In vivo, such preferences were only significant for Granulicatella adiacens (more prevalent on BE) and Fusobacterium nucleatum subsp. animalis (more prevalent on composites). On DNA sequence level, there were no significant differences between the biofilm communities on GF and GF+C. Conclusion: We found that the oral microbiome showed an increased richness when grown on various composites compared to BE in vitro, but otherwise changed only slightly independent of the in vivo or in vitro condition. Our new ex vivo biofilm model might be useful for pre-clinical testing of preventive strategies.

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“…However, a recent study showed a different insight into the action mechanism of Carolacton. A group of researchers investigated that Carolacton targets FolD [Fu et al, 2017] which is a key enzyme from the folate-dependent C1 metabolism. Folate, also known as vitamin B 9 , is an essential co-factor in every cell, but it is produced only by bacteria and plants [Green et al, 2007].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Restorative Materials Containing Preventive Additives in a Secondary Caries Model in vitro

et al. 2019

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The incorporation of antibacterial agents into dental restorative materials is a promising strategy for secondary caries prevention. Previously, Carolacton affected Streptococcus mutans biofilm formation on composite materials in vitro. The present study evaluated secondary caries formation adjacent to Carolacton-containing composites and conventional restorative materials using an artificial biofilm model. Standardized cavities were prepared in bovine dentin-enamel samples (n = 175) and restored with various dental materials (Tetric EvoCeram [T], GrandioSo composite without [G] and with Carolacton [GC], Grandio Flow without [F] and with Carolacton [FC], GrandioSo containing sodium fluoride [GNaF], and Ketac Fil [K]). After artificial aging, S. mutans was grown on the samples for 7 days. The investigation of gap sizes and secondary caries formation was performed using confocal laser scanning microscopy and transversal microradiography. Median gap size in enamel was 9.4 µm (interquartile range 7.9–12.7). Compared to all other groups significant differences in gap sizes could be observed for Ketac Fil (p < 0.001; Mann-Whitney test). Only GrandioSo composite containing 30% sodium fluoride and Ketac Fil showed significantly smaller lesion areas in enamel (p < 0.001; Mann-Whitney test) than all other groups which was confirmed by the mineral loss data (p < 0.001; Mann-Whitney test). Based on the present in vitro results, it seems that Carolacton-containing composite in the current formulation within the shown simplified monoculture biofilm model is not able to prevent caries formation compared to fluoride-releasing restorative materials.

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The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD

Cited by 73 publications

References 47 publications

Down‐regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle‐related genes

Down‐regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle‐related genes

Deep sequencing of biofilm microbiomes on dental composite materials

Evaluation of Restorative Materials Containing Preventive Additives in a Secondary Caries Model in vitro

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