Resveratrol Affects Sphingolipid Metabolism in A549 Lung Adenocarcinoma Cells

Abstract

Resveratrol is a naturally occurring polyphenol which has various beneficial effects, such as anti-inflammatory, anti-tumor, anti-aging, antioxidant, and neuroprotective effects, among others. The anti-cancer activity of resveratrol has been related to alterations in sphingolipid metabolism. We analyzed the effect of resveratrol on the enzymes responsible for accumulation of the two sphingolipids with highest functional activity—apoptosis promoting ceramide (CER) and proliferation-stimulating sphingosine-1-phosphate (S1P)—in human lung adenocarcinoma A549 cells. Resveratrol treatment induced an increase in CER and sphingosine (SPH) and a decrease in sphingomyelin (SM) and S1P. Our results showed that the most common mode of CER accumulation, through sphingomyelinase-induced hydrolysis of SM, was not responsible for a CER increase despite the reduction in SM in A549 plasma membranes. However, both the activity and the expression of CER synthase 6 were upregulated in resveratrol-treated cells, implying that CER was accumulated as a result of stimulated de novo synthesis. Furthermore, the enzyme responsible for CER hydrolysis, alkaline ceramidase, was not altered, suggesting that it was not related to changes in the CER level. The enzyme maintaining the balance between apoptosis and proliferation, sphingosine kinase 1 (SK1), was downregulated, and its expression was reduced, resulting in a decrease in S1P levels in resveratrol-treated lung adenocarcinoma cells. In addition, incubation of resveratrol-treated A549 cells with the SK1 inhibitors DMS and fingolimod additionally downregulated SK1 without affecting its expression. The present studies provide information concerning the biochemical processes underlying the influence of resveratrol on sphingolipid metabolism in A549 lung cancer cells and reveal possibilities for combined use of polyphenols with specific anti-proliferative agents that could serve as the basis for the development of complex therapeutic strategies.

Effect of Quercetin and Fingolimod, Alone or in Combination, on the Sphingolipid Metabolism in HepG2 Cells

“…However, the level of S1P was gradually decreased in the following order of treatment: quercetin, fingolimod, quercetin + fingolimod, showing that the combined treatment produced a stronger effect on the level of S1P compared to each one of the individual treatments (Figure 4). Accordingly, in our previous studies we observed a decrease in the level of S1P in resveratrol-treated A549 lung adenocarcinoma cells [32]. However, Charytoniuk et al reported an increase of S1P in resveratrol-treated HepG2 cells in a lipid overload state, which might be related to a more complicated lipid metabolism in cells overloaded with lipid precursors [10].…”

“…There is evidence that another polyphenol, resveratrol, significantly affects the major sphingolipid metabolites in HepG2 cells [10]. What is more, in our recent paper, we reported that the effect of resveratrol on the lipid metabolism in A549 lung cancer cells is potentiated by combined treatment with fingolimod [32], which is why the latter was included in the present experiments. As evident from Figure 2 treatment of HepG2 cells with quercetin and fingolimod, alone or in combination, induced different effects on the level of SM.…”

Mechanisms of Arachidonic Acid In Vitro Tumoricidal Impact

“…Lung adenocarcinoma A-549 cells showed resistance to Triton X-100-mediated SM extraction before and after 50 μM/30 min ARA exposure. The SM membrane content of this cell line was also marginally affected following treatment with 100 μM resveratrol for 24 h [ 51 ].…”

Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies

“…Resveratrol is one of the most studied polyphenols derived from plants. It modulates the SL pathway in a variety of cancers, including hepatocellular carcinoma, gastric cancer, lung adenocarcinoma, and leukemia [ 175 , 176 , 177 , 178 ]. Resveratrol was previously shown to cause apoptosis in HL-60 cells due to the accumulation of ceramides and a reduction in SPHK1 and GCS expression [ 178 ].…”