Nicotinamide N‐methyltransferase gene silencing enhances chemosensitivity of melanoma cell lines

Campagna, Roberto; Salvolini, Eleonora; Pompei, Veronica; Pozzi, Valentina; Salvucci, Alessia; Molinelli, Elisa; Brisigotti, Valerio; Sartini, Davide; Campanati, Anna; Offidani, Annamaria; Emanuelli, Monica

doi:10.1111/pcmr.12993

Cited by 35 publications

(30 citation statements)

References 46 publications

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“…Some researchers have questioned the relevance of the application of methyl donors even from a dietary source, implying that, in Nicotinamid N-methyl-transferase (NNMT)-overexpressing tumors, methyl donors might fuel the NNMT enzyme causing a worse prognosis. They refer to studies where silenced NNMT has resulted in decreased migration, invasion, proliferation, and increased chemosensitivity [ 50 ], and also that NNMT expression is enhanced in cancer stem cells [ 51 ]. The NNMT enzyme takes a methyl group from S-adenosyl-L-methionine (SAM) and adds it to nicotinamide (NA), generating methyl-nicotinamid (MNA) and S-adenosyl-L-homocysteine as a result [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line

Kiss

Forika

Dank

et al. 2022

IJMS

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Pancreatic cancer is an aggressive malignancy with high metastatic potential. There are several lifestyle-related determinants in its etiology, including diet. Methyl donors are dietary micronutrients which play an important role in fueling vital metabolic pathways, and as bioactive food components provide methyl groups as substrates and cofactors. The imbalanced nutritional status of methyl donors has recently been linked to pathological conditions. Therefore, we hypothesized that dietary methyl donors may improve the physiology of cancer patients, including those with pancreatic cancer, and could be used for intervention therapy. In this study, methyl-donor treatment (L-methionine, choline chloride, folic acid and vitamin B12) of an aggressive pancreatic adenocarcinoma cell line (Panc-1) resulted in significantly increased p21WAF1/Cip1 cyclin-dependent kinase inhibitor levels, along with apoptotic SubG1 fractions. At the same time, phospho-Erk1/2 levels and proliferation rate were significantly reduced. Though methyl-donor treatments also increased the pro-apoptotic protein Bak, Puma and Caspase-9, it failed to elevate cleaved Caspase-3 levels. In addition, the treatment significantly reduced the production of the pro-inflammatory cytokine IL-17a and the transcription factor NFkB. Similarly, a significant decrease in VEGF and SDF-1a levels were detected, which may indicate reduced metastatic potential. As expected, E-cadherin expression was inversely associated with these changes, showing elevated expression after methyl-donor treatment. In summary, we found that methyl donors may have the potential to reduce aggressive and proliferative phenotype of Panc-1 cells. This suggests a promising role of dietary methyl donors for complementing relevant cancer therapies, even in treatment-resistant pancreatic adenocarcinomas.

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Section: Discussionmentioning

confidence: 99%

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line

Kiss

Forika

Dank

et al. 2022

IJMS

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“…In another study, the functional role of NNMT was investigated through shRNAmediated silencing of the enzyme in the melanoma cell lines A375 and WM-115 [92]. Following NNMT knockdown, cell proliferation, migration, and chemosensitivity were evaluated.…”

Section: Involvement Of Nnmt In Scmentioning

confidence: 99%

“…A large number of studies were focused on exploring the impact of NNMT downregulation in several cancer models, leading to the discovery that the suppression of this enzyme prevents cancer cell proliferation, invasion, and metastasis, as well as chemoresistance [50,92]. Moreover, it was suggested that the enzyme may contribute to the radioresistance of cancer cells [96,97].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers

Campagna

Pozzi

Salvolini

et al. 2021

Cancers

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Skin cancers (SC) collectively represent the most common type of malignancy in white populations. SC includes two main forms: malignant melanoma and non-melanoma skin cancer (NMSC). NMSC includes different subtypes, namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Merkel cell carcinoma (MCC), and keratoacanthoma (KA), together with the two pre-neoplastic conditions Bowen disease (BD) and actinic keratosis (AK). Both malignant melanoma and NMSC are showing an increasing incidence rate worldwide, thus representing an important challenge for health care systems, also because, with some exceptions, SC are generally characterized by an aggressive behavior and are often diagnosed late. Thus, identifying new biomarkers suitable for diagnosis, as well as for prognosis and targeted therapy is mandatory. Nicotinamide N-methyltransferase (NNMT) is an enzyme that is emerging as a crucial player in the progression of several malignancies, while its substrate, nicotinamide, is known to exert chemopreventive effects. Since there is increasing evidence regarding the involvement of this enzyme in the malignant behavior of SC, the current review aims to summarize the state of the art as concerns NNMT role in SC and to support future studies focused on exploring the diagnostic and prognostic potential of NNMT in skin malignancies and its suitability for targeted therapy.

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“…Similar efficacy and toxicity was registered for another alkylating agent, temozolomide. Moreover, the application of alkylating agents such as DTIC in the combined therapy did not show any survival benefits for patients in comparison with monochemiotherapy [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Anandamide-Modulated Changes in Metabolism, Glycosylation Profile and Migration of Metastatic Melanoma Cells

Sobiepanek

Milner-Krawczyk

Musolf

et al. 2022

Cancers

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An effective therapy for advanced melanoma, a skin cancer with the highest mortality, has not yet been developed. The endocannabinoid system is considered to be an attractive target for cancer treatment. The use of endocannabinoids, such as anandamide (AEA), is considered to be much greater than as a palliative agent. Thus, we checked its influence on various signaling pathways in melanoma cells. Our investigation was performed on four commercial cell lines derived from different progression stages (radial WM35 and vertical WM115 growth phases, lymph node WM266-4 metastasis, solid tumor A375-P metastasis). Cell viability, glucose uptake, quantification of reactive oxygen species production, expression of selected genes encoding glycosyltransferases, quantification of glycoproteins production and changes in the glycosylation profile and migration, as well as in cell elastic properties were analyzed. The cell glycosylation profile was investigated using the biophysical profiling method—the quartz crystal microbalance with dissipation monitoring (QCM-D). Anandamide treatment of only metastatic cells resulted in: an increase in the cell metabolism, a decrease in GFAT-1 and DPM1 expression, followed by a decrease in L1-CAM glycoprotein production, which further influenced the reduction in the cell glycosylation profile and migration. Considering our results, AEA usage is highly recommended in the combined therapy of advanced melanoma.

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Nicotinamide N‐methyltransferase gene silencing enhances chemosensitivity of melanoma cell lines

Cited by 35 publications

References 46 publications

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line

Beyond Nicotinamide Metabolism: Potential Role of Nicotinamide N-Methyltransferase as a Biomarker in Skin Cancers

Anandamide-Modulated Changes in Metabolism, Glycosylation Profile and Migration of Metastatic Melanoma Cells

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