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

Zhang,Ling; Huang,Daobin; Shao,Decui; Liu,Hui; Zhou,Qing; Gui,Shuyu; Wei,Wei; Wang,Yuan

doi:10.3892/or.2018.6436

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

Authors:
- Ling Zhang
- Daobin Huang
- Decui Shao
- Hui Liu
- Qing Zhou
- Shuyu Gui
- Wei Wei
- Yuan Wang
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Affiliations: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, P.R. China, School of Medical Information, Wannan Medical College, Wuhu, Anhui 241002, P.R. China, Laboratory of Cell Electrophysiology, Wannan Medical College, Wuhu, Anhui 241002, P.R. China, Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Respiratory Medicine, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022, P.R. China
Published online on: May 16, 2018 https://doi.org/10.3892/or.2018.6436
Pages: 518-526

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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 significantly hindered HepG2 cell migration, and that this was accompanied by the phosphorylation of p38‑MAPK (mitogen‑activated protein kinase). Mechanistically, the MAPK‑specific 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, significantly 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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