Abstract 5252: Salsolinol suppresses the STAT3-EMT axis in liver carcinogenesis

Abstract Liver cancer is one of the most common malignancies and a leading cause of death worldwide. However, it is still very difficult to treat and prevent liver cancer. Salsolinol (SAL) is an endogenous catechol isoquinoline generated by the condensation of dopamine with acetaldehyde, a major metabolite of ethanol. In the present study, we found that SAL inhibited the phosphorylation, dimerization, and subsequent nuclear translocation of STAT3 in a concentration-dependent manner in SK-Hep1 cells, a hepatic carcinoma cell line. SAL suppressed the expression of Cdk 4 and Cyclin D1, the major target protein of STAT3, and induced the cell cycle arrest at Go/G1 phase. However, SAL induced the expression of STAT1 in SK-Hep1 cells. In addition, SAL enhanced the expression of the cell cycle regulators such as p53 and p21 in SK-Hep1 cells. Epithelial-mesenchymal transition (EMT) promotes tumor invasion and metastasis in malignancies through STAT3 activation. SAL induced the expression of E-cadherin while suppressing the expression of Snail, N-cadherin, and Slug, which are related to EMT. SAL inhibited the migration of SK-Hep1 cells by suppressing the expression of MMP-9 and MMP-2. Furthermore, intraperitoneal injection of SAL reduced the number of tumors in the diethylnitrosamine (DEN)-induced liver carcinogenesis model without affecting the body weight change. Proliferative markers PCNA and KI-67 and p-STAT3 were down-regulated in the SAL-injected mice liver cancer tissue. The plasma level of alpha-fetoprotein, a tumor marker in the blood, was also reduced in the SAL-injected mice. Interestingly, SAL injection significantly reduced the anxiety-like behavior without affecting the locomotive activities in the DEN-induced hepatocellular carcinoma mouse model. Moreover, SAL injection recovered tyrosine hydroxylase, a key enzyme for producing dopamine from tyrosine in the substantia nigra compacta of DEN-treated mice. Together, SAL inhibits STAT3 signaling, thereby suppressing the cell cycle progression and EMT in SK-Hep1 cells, which may account for its anti-depressant and anti-carcinogenic activity in DEN-induced liver carcinogenesis. Citation Format: Hyeon Jeong Oh, Seah Park, Hong-Kyung Yang, Hoon Ryu, Young-Joon Surh, Dae-Yong Kim, Hye-Kyung Na. Salsolinol suppresses the STAT3-EMT axis in liver carcinogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5252.