Upregulation by duloxetine of the transforming growth factor‐α‐induced migration of hepatocellular carcinoma cells via enhancement of the c‐Jun N‐terminal kinase activity

Abstract

AbstractDuloxetine, a selective reuptake inhibitor for serotonin and norepinephrine, is a medication widely used for major depression. Currently, duloxetine is also recommended for pain related to chemotherapy‐induced peripheral neuropathy or cancer. Previously, we showed that transforming growth factor‐α (TGF‐α) induces the migration of human hepatocellular carcinoma (HCC)‐derived HuH7 cells through the activation of c‐Jun N‐terminal kinase (JNK), p38 mitogen‐activated protein kinase (MAPK) and AKT. In the present study, we investigate whether duloxetine affects cell migration and its mechanism. Duloxetine significantly enhanced the TGF‐α‐induced migration of HuH7 cells. Fluvoxamine and sertraline, specific inhibitors of serotonin reuptake, also upregulated the TGF‐α‐induced cell migration. On the contrary, reboxetine, a specific norepinephrine reuptake inhibitor, failed to affect cell migration. Duloxetine significantly amplified the TGF‐α‐stimulated phosphorylation of JNK, but not p38 MAPK and AKT. In addition, fluvoxamine and sertraline, but not reboxetine, enhanced the phosphorylation of JNK. SP600125, a JNK inhibitor, suppressed the enhancement by duloxetine, fluvoxamine, or sertraline of TGF‐α‐induced migration of HuH7 cells. Taken together, our results strongly suggest that duloxetine strengthens the TGF‐α‐induced activation of JNK via inhibition of serotonin reuptake in HCC cells, leading to the enhancement of cell migration.