The aryl hydrocarbon receptor ligand ITE inhibits cell proliferation and migration and enhances sensitivity to drug‐resistance in hepatocellular carcinoma

• Published in: Journal of cellular physiology 2021-01, Vol.236 (1), p.178-192
• Main Authors: Zhang, Xiaoqian, He, Bin, Chen, Ermei, Lu, Juan, Wang, Jie, Cao, Hongcui, Li, Lanjuan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE); AKT protein; Anticancer properties; Antitumor activity; Apoptosis; Aromatic compounds; aryl hydrocarbon receptor; Biocompatibility; Carbonyl compounds; Carbonyls; Carboxylic acids; Cell proliferation; Chemical compounds; Hepatocellular carcinoma; Hydrocarbons; Indoles; invasion; Ligands; Liver cancer; migration; Pharmacology; Receptors; resistance; sensitivity; Sensitivity enhancement; Toxicity; Xenografts; Xenotransplantation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29832

Aryl hydrocarbon receptor (AHR), a ligand‐activated transcription factor, is considered as a crucial gene during tumor formation and progress. Among various ligands, 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE) has been evaluated to share a broad spectrum of biological activities. However, the specific effects and potential mechanisms of ITE against hepatocellular carcinoma remain unclear. Here we explored whether ITE exerted antitumor activity against hepatocellular carcinoma (HCC) cells and its potential mechanisms in vitro and in vivo. We found that ITE could markedly inhibit proliferation of HCCLM3 and SMMC‐7721 cells and induce G0/G1 arrest and apoptosis with alterations of expressions of the related proteins. Also, ITE could prohibit the process of migration and invasion evaluated by transwell assay. Moreover, ITE exhibited remarkable capability to repress the growth of HCCLM3‐SR cells and induce apoptosis in contrast to sorafenib. Additionally, ITE also showed potent antitumor activity against the HCCLM3 xenograft by prohibiting tumor growth without any toxicity to mice. Mechanistically, AHR activation by ITE was attributed to inhibition of HCC cells as AHR knockdown would abolish ITE‐induced suppression in HCC cells, and overexpression of AHR would potentiate antitumor activity regulated by ITE. Our data suggested that ITE manifested a marked antitumor effect against HCC cells both in vitro and in vivo via AHR activation mainly through inducing G1/G0 arrest and apoptosis and inhibiting the process of migration and invasion. Furthermore, we also found the PI3K/AKT pathway was involved in sorafenib‐induced resistance and ITE could restore sensitivity by suppressing the PI3K/AKT pathway. Collectively, our study revealed that ITE would be a promising therapeutic agent to deal with HCC and an alternative for drug‐resistant HCC. Our data suggested that 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE) manifested a marked antitumor effect against hepatocellular carcinoma cells both in vitro and in vivo via aryl hydrocarbon receptor activation mainly through inducing G1/G0 arrest and apoptosis and inhibiting processes of migration and invasion. Furthermore, we also found the PI3K/AKT pathway was involved in sorafenib induced resistance and ITE could restore sensitivity by suppressing the PI3K/AKT pathway.