Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma

Abstract

Overexpressed EphB4 conduce to tumor development and is regarded as a potential anticancer target. Homoharringtonine (HHT) has been approved for hematologic malignancies treatment, but its effect on hepatocellular carcinoma (HCC) has not been studied. This study elucidated HHT could restrain the proliferation and migration of HCC via an EphB4/β-catenindependent manner. We found that the antiproliferative activity of HHT in HCC cells and tumor xenograft was closely related to EphB4 expression. In HepG2, Hep3B and SMMC-7721 cells, EphB4 overexpression or EphrinB2 Fc stimulation augmented HHT-induced inhibitory effect on cell growth and migration ability, and such effect was abrogated when EphB4 was knocked down. The similar growth inhibitory effect of HHT was observed in SMMC-7721 and EphB4 + /SMMC-7721 cells xenograft in vivo. Preliminary mechanistic investigation indicated that HHT directly bound to EphB4 and suppressed its expression. Data obtained from HCC patients revealed increased β-catenin expression and a positive correlation between EphB4 expression and β-catenin levels. HHT-induced EphB4 suppression promoted the phosphorylation and loss of β-catenin, which triggered regulation of β-catenin downstream signaling related to migration, resulting in the reversion of EMT in TGF-β-induced HepG2 cells. Collectively, this study provided a groundwork for HHT as an effective antitumor agent for HCC in an EphB4/ β-catenin-dependent manner.

Homoharringtonine inhibits the progression of hepatocellular carcinoma by suppressing the PI3K/AKT/GSK3β/Slug signaling pathway

“…In recent years, HHT has also been used in research on various solid tumors, such as bladder, kidney, lung, and colorectal cancer [21][22][23][24]. Recent studies have reported that HHT suppresses tumor proliferation and migration by regulating EphB4--catenin loss in HCC [25]. In this study, we also observed the inhibitory effect of HHT on the growth and metastasis of HCC in vivo and in vitro.…”

Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways

“…It has been reported that homoharringtonine down-regulates EphB4 expression to mediate phosphorylation and degradation of β-catenin, impairing HCC progression. 115 The trans-chalcone is another anti-tumor agent that can reduce β-catenin expression in impairing proliferation of HCC cells. 116 These examples were provided to show how β-catenin activation and inactivation can affect survival rate and growth of HCC cells and in the next sections, we specifically discussed targeting β-catenin with anti-cancer agents in HCC therapy.…”

Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1

“…After three repeats of screening, information on the primary positive candidates was obtained from the KCB. Several chemicals previously known to regulate metastasis signalings were identified, including vinblastine, bufalin, tomatine, homoharringtonine, and mogroside IV [ 16 , 17 , 18 , 19 , 20 ], thus, underscoring the validity of our screening. Cytotoxicity tests were performed using novel candidate chemicals to exclude chemicals that could induce strong cell death.…”