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Homoharringtonine Exerts Anti-tumor Effects in Hepatocellular Carcinoma Through Activation of the Hippo Pathway.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer with a mortality rate of approximately 3-6/100,000 and is the third leading cause of cancer-related death worldwide. Although several small-molecule drugs have been developed for the treatment of HCC, the choice of an agent for patients who require systemic chemotherapy at an advanced stage is still limited. The Hippo pathway is an evolutionarily conserved tumor suppressive pathway commonly dysregulated in HCC, which makes it a promising target for anti-HCC therapies. Homoharringtonine (HHT) is an FDA-approved anti-leukemia drug with proven strong anti-tumor activity in solid tumors. In this study, we found that HHT could significantly inhibit HCC cell growth by suppressing cell proliferation and colony formation. Moreover, HHT repressed cell invasion and migration remarkably. Additionally, HHT induced cell cycle arrest at S phase and promoted apoptosis. Most importantly, we showed that HHT-induced apoptosis was a consequence of the Hippo pathway activation. Consistently, the MST1/2 inhibitor, XMU-MP-1, could restore cell viability and reverse HHT-induced cell apoptosis. Furthermore, in vivo results confirmed the tumor inhibitory effect of HHT. Taken together, our findings suggest that HHT is a potential alternative therapeutic agent for the treatment of HCC.

SUBMITTER: Wang H

PROVIDER: S-EPMC7943857 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Homoharringtonine Exerts Anti-tumor Effects in Hepatocellular Carcinoma Through Activation of the Hippo Pathway.

Wang Haina H Wang Rui R Huang Dan D Li Sihan S Gao Beibei B Kang Zhijie Z Tang Bo B Xie Jiajun J Yan Fanzhi F Liang Rui R Li Hua H Yan Jinsong J

Frontiers in pharmacology 20210224

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer with a mortality rate of approximately 3-6/100,000 and is the third leading cause of cancer-related death worldwide. Although several small-molecule drugs have been developed for the treatment of HCC, the choice of an agent for patients who require systemic chemotherapy at an advanced stage is still limited. The Hippo pathway is an evolutionarily conserved tumor suppressive pathway commonly dysregulated in HCC, which ma ...[more]

PMID: 33716735

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Project description:BackgroundAbnormal expression or distribution of connexin 32 (Cx32) is associated with hepatocarcinogenesis, but the role of Cx32 and the underlying mechanisms are still unclear.MethodsThe expression level of Cx32 in 96 hepatocellular carcinoma (HCC) specimens was determined using western blotting and immunohistochemistry. The correlation between Cx32 expression and clinicopathological parameters was analyzed. The cell apoptosis rate was examined using flow cytometry and western blotting. The role of Cx32 in the Src kinase and epidermal growth factor receptor (EGFR) signaling pathways was measured by quantitative real-time PCR, western blotting and coimmunoprecipitation (CO-IP). The effect of Cx32 overexpression on the streptonigrin (SN)-induced tumor growth suppression and apoptosis was assessed in nude mice.ResultsOur study showed that overexpressed Cx32 accumulated in the cytoplasm and that Cx32-containing gap junctions (GJs) were nearly absent in HCC specimens. Upregulated Cx32 expression was highly correlated with advanced tumor-node-metastasis (TNM) stage and poor tumor differentiation and was an independent predictive marker for poor prognosis in HCC. Overexpression of Cx32 significantly inhibited SN-induced apoptosis by activating the EGFR signaling pathway in vitro and in vivo. Moreover, the expression levels of Cx32 and EGFR were positively correlated in HCC specimens. The CO-IP experiments demonstrated that Cx32 could bind to Src kinase, and the western blotting results revealed that Cx32 increased the levels of EGFR and p-EGFR by upregulating Src expression.ConclusionThe present study demonstrated that overexpressed and internalized Cx32 was associated with advanced TNM stage and poor tumor differentiation and predicted poor prognosis in HCC. Cx32 facilitated HCC progression by blocking chemotherapy-induced apoptosis in vitro and in vivo via interacting with Src and thus promoting the phosphorylation of EGFR, subsequently activating the EGFR signaling pathway. Cx32 may be a potential biomarker and a new therapeutic target for HCC.

Project description:BackgroundIt is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly.MethodsWe determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N?=?40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models.ResultsOur results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of ?-catenin and a repressed GSK3? activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of ?-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of ?-catenin by siRNA approach.ConclusionThis study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.

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Homoharringtonine Exerts Anti-tumor Effects in Hepatocellular Carcinoma Through Activation of the Hippo Pathway.

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Homoharringtonine Exerts Anti-tumor Effects in Hepatocellular Carcinoma Through Activation of the Hippo Pathway.

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