alpha-cyano-4-hydroxycinnamate impairs pancreatic cancer cells by stimulating the p38 signaling pathway

作者：Schoenrogge Maria; Kerndl Hagen; Zhang Xianbin; Kumstel Simone; Vollmar Brigitte; Zechner Dietmar^*

来源：Cellular Signalling, 2018, 47: 101-108.

DOI：10.1016/j.cellsig.2018.03.015

Multiple studies are currently targeting dysregulated cancer cell metabolism with distinct combinations of inhibitors. In this study, we evaluated in pancreatic cancer cells metformin, which blocks oxidative phosphorylation, in combination with alpha-cyano-4-hydroxycinnamate, which has been reported to inhibit the export of lactate from the cytosol. The combination of metformin with alpha-cyano-4-hydroxycinnamate had a major inhibitory effect on the migration of 6606PDA cells. Monotherapy with alpha-cyano-4-hydroxycinnamate and especially the combination with metformin also caused significant inhibition of cell proliferation and induced cell death. alpha-cyano-4-hydroxycinnamate in combination with metformin reduced the export of lactate significantly, whereas alpha-cyano-4-hydroxycinnamate monotherapy only modestly influenced lactate export. None of these two drugs inhibited the expression of distinct glycolytic enzymes. Interestingly, alpha-cyano-4-hydroxycinnamate rather inhibited the ERK and very strongly stimulated the p38 signaling pathway in 6606PDA as well as in 7265PDA cells. In addition, the inhibition of the p38 signaling pathway by PH-797804 partially reversed the effect of alpha-cyano-4-hydroxycinnamate on cell apoptosis in both cell lines. We conclude that alpha-cyano-4-hydroxycinnamate monotherapy and especially the combinatorial therapy with metformin has strong anti-cancerous effects. alpha-cyano-4-hydroxycinnamate causes cancer cell apoptosis by a novel mechanism for this drug, namely the stimulation of the p38 signaling pathway.

• 出版日期2018-7