Leptin-derived peptides block leptin-induced proliferation by reducing expression of pro-inflammatory genes in hepatocellular carcinoma cells

Abstract The obesity-regulated gene, leptin, is essential for diet. Leptinresistance causes obesity and related diseases. Certain types of diet are able to decrease leptinresistance. However, leptinhas been shown to be correlated with inflammation and stimulate proliferation of various cancers. Two synthetic leptinderivatives ( mimetics), OB3 and [D-Leu-4]-OB3, show more effective than leptinin reducing obesity and diabetes in mouse models. OB3 inhibits leptin-induced proliferation in ovarian cancer cells. However, effects of these mimeticsin hepatocellular carcinoma (HCC) have not been investigated. In the present study, we examined the effects of OB3 and [D-Leu-4]-OB3 on cell proliferation and gene expressions in human HCC cell cultures. In contrast to what was reported for leptin, OB3 and [D-Leu-4]-OB3 reduced cell proliferation in hepatomas. Both OB3 and [D-leu-4]-OB3 stimulated expression of pro-apoptotic genes. Both compounds also inhibited expressions of pro-inflammatory, proliferative and metastatic genes and PD-L1expression. In combination with leptin, OB3 inhibited leptin-induced cell proliferation and expressions of pro-inflammation-, and proliferation-related genes. Furthermore, the OB3 peptide inhibited phosphoinositide 3-kinase(PI3K) activation which is essential for leptin-induced proliferation in HCC. These results indicate that OB3 and [D-Leu-4]-OB3 may have the potential to induce anti- leptin-related inflammation and proliferation in HCC cells.