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

• Published in: Cell biochemistry and function 2023-10, Vol.41 (7), p.814-822
• Main Authors: Matsushima‐Nishiwaki, Rie, Kamoi, Shota, Kozawa, Osamu
• Format: Article
• Language: English
• Subjects: AKT protein; Amplification; Analgesics; Antidepressants; Cancer; Cell activation; Cell adhesion & migration; Cell migration; Chemotherapy; Duloxetine; Fluvoxamine; Growth factors; Hepatocellular carcinoma; JNK protein; Kinases; Liver cancer; MAP kinase; Norepinephrine; Pain; Peripheral neuropathy; Phosphorylation; Reboxetine; Serotonin; Sertraline; Transforming growth factor-a
• ISSN: 0263-6484; 1099-0844
• DOI: 10.1002/cbf.3831

Duloxetine, 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. Duloxetine, a selective serotonin‐norepinephrine reuptake inhibitor, is currently used not only as an antidepressant, but also as an analgesic for treating various pain including the pain related to cancer. In this study, we showed for the first time that duloxetine significantly enhanced transforming growth factor‐α‐stimulated activation of c‐Jun N‐terminal kinase via reuptake inhibition of serotonin but not norepinephrine in human hepatocellular carcinoma (HCC)‐derived HuH7 cells, resulting in amplifying the cell migration. This finding may provide a cautionary note when using duloxetine for patients with HCC.