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

Abstract

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.

The Effect of Dietary Methyl-Donor Intake and Other Lifestyle Factors on Cancer Patients in Hungary

“…It was only in the case of pancreatic cancer patients that a higher (mid) level of intake of methionine and summative amounts of methyl-donor intakes were found effective for significantly better survival, which could reflect the nature of this type of disease with a poorer absorption of vitamins in the small intestine. These results are also supported by our previous cell-based studies, where amounts around the RDA of methyl-donors were efficient to reduce breast, lung and pancreatic cancer cell growth and inflammation, induce apoptosis and activate related signal pathways [ 23 , 24 , 25 , 26 ]. Unfortunately, there was no information about the utility of the RDA intake of any dietary components similar to “drug efficacy data” (i.e., pharmacokinetic data), probably as the former are essential building blocks of the cells in the human body.…”

“…Lifestyle factors including nutrition, smoking and drinking habits, physical activity, stress levels or socioeconomic state and behavior have a significant impact on cancer risk and development [ 27 , 28 , 29 , 30 ]. In our previous works, we investigated whether the intake of methyl-donor B vitamin could influence the risk of colorectal cancer [ 2 ] and also studied the methyl-donor-induced changes in the growth and apoptosis of tumor cells, and in other cellular processes [ 23 , 24 , 25 , 26 ]. In our recent research, we randomly selected breast, colorectal and pancreatic cancer patients and applied a food frequency questionnaire (FFQ) and a diet diary to summarize the socioeconomic status and lifestyle factors as well as evaluate whether there is an impact of methyl-donor intake on overall survival.…”

“…In a systematic review and meta-analysis, we also found that the appropriate intake of B vitamins, which are also dietary methyl-donors, may reduce the risk of colorectal cancer [ 2 ]. As such, we studied the effect of methyl-donors in breast, lung and pancreatic cancer cell lines and found that methyl-donors may inhibit cancer cell growth and progression as well as inflammatory signals originating from cancer cells [ 23 , 24 , 25 , 26 ].…”

Citric acid promotes SPARC release in pancreatic cancer cells and inhibits the progression of pancreatic tumors in mice on a high‐fat diet

“…Additionally, our study indicated that the NFκB pathway plays a role in the pancreatic cancer cell proliferation cycle, promotes EMT, and enhances the invasive potential of pancreatic cancer cells [39]. Our study revealed inhibition of the NFκB pathway reduced cell proliferation and tumorigenic potential.…”