IL-37 induces autophagy in hepatocellular carcinoma cells by inhibiting the PI3K/AKT/mTOR pathway

• Published in: Molecular immunology 2017-07, Vol.87, p.132-140
• Main Authors: Li, Ting-Ting, Zhu, Di, Mou, Tong, Guo, Zhen, Pu, Jun-Liang, Chen, Qing-Song, Wei, Xu-Fu, Wu, Zhong-Jun
• Format: Article
• Language: English
• Subjects: Apoptosis - physiology; Autophagy - physiology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line; Cell Line, Tumor; Cell Proliferation - physiology; Hep G2 Cells; Humans; Insulin-Like Growth Factor I - metabolism; Interleukin-1 - metabolism; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - physiology; Proto-Oncogene Proteins c-akt - metabolism; Repressor Proteins - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction - physiology; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2017.04.010

Autophagy is an intracellular "self-eating" process that is closely related to inflammation and cellular immunity. New studies indicate that autophagy is also involved in tumor suppression. The anti-inflammatory cytokine interleukin-37 (IL-37) has been shown to have tumor-suppressive abilities in hepatocellular carcinoma (HCC). Notably, autophagy appears to play a dual role in the development of HCC and may be involved in both tumorigenesis and tumor suppression. However, the potential role of IL-37 in autophagy is currently unknown. In this study, we investigated the effect of IL-37 on autophagy in multiple HCC cell lines. In doing so, we found that IL-37 inhibits proliferation in HCC cells and also induces autophagy and apoptosis in the SMMC-7721 and Huh-7 cell lines. Further experiments revealed that IL-37 treatment reduced the levels of phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), phosphorylated p70 ribosomal protein s6 kinase (p-p70S6K) and phosphorylated 4E-binding protein 1 (4E-BP1). Moreover, treatment with an AKT agonist, insulin-like growth factor 1 (IGF-1), reversed these IL-37-mediated effects on autophagy, and treatment with an phosphoinositide-3-kinase (PI3K)/AKT inhibitor, LY294002, mimicked the effects of IL-37. Taken together, these results indicate that IL-37 regulates autophagy in SMMC-7721 and Huh-7 cells via inhibition of the PI3K/AKT/mTOR signaling pathway.