Fenretinide inhibits the proliferation and migration of human liver cancer HepG2 cells by downregulating the activation of myosin light chain kinase through the p38-MAPK signaling pathway

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Abstract

N-(4-hydroxyphenyl)retinamide (4-HPR or fenretinide), which is a synthetic analog of all-trans retinoic acid (ATRA), effectively inhibits the growth of several types of tumor cells; however, its molecular mechanism remains unclear. We found that 4-HPR altered the morphology of human liver cancer HepG2 cells and also inhibited their proliferation and suppressed the colony formation in a dose-and time-dependent manner. A wound healing assay revealed that 4-HPR signifcantly hindered HepG2 cell migration, and that this was accompanied by the phosphorylation of p38-MAPK (mitogen-activated protein kinase). Mechanistically, the MAPK-specifc inhibitor SB203580 attenuated the inhibitory effects of 4-HPR on the migration of HepG2 cells. Moreover, we also observed that 4-HPR inhibited the activation and expression of myosin light chain kinase (MLCK) in HepG2 cells. Simultaneously, 4-HPR lowered the expression of F-actin and promoted the expression of E-cadherin. ML-7, a selective inhibitor of MLCK, signifcantly inhibited the migration of HepG2 cells while increasing the phosphorylation of p38-MAPK and the expression of E-cadherin, and decreasing the activation of MLCK and the expression of F-actin. In conclusion, 4-HPR inhibited the proliferation and migration of HepG2 cells, and p38-MAPK plays an important role in regulating these 4-HPR effects by reducing the activation of MLCK. The present study suggests that 4-HPR may be a potent antimetastatic agent.

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Zhang, L., Huang, D., Shao, D., Liu, H., Zhou, Q., Gui, S., … Wang, Y. (2018). Fenretinide inhibits the proliferation and migration of human liver cancer HepG2 cells by downregulating the activation of myosin light chain kinase through the p38-MAPK signaling pathway. Oncology Reports, 40(1), 518–526. https://doi.org/10.3892/or.2018.6436

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