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An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy.

ABSTRACT: The precise role of Epidermal Growth Factor Receptor (EGFR) in Hepatocellular carcinoma (HCC) cells is unknown and EGFR inhibitors have not achieved positive clinical results. The rapid and drastic internalization of EGFR has been proved to successfully treat EGFR inhibitor-resistant patients in recent clinical trials. Here, the anti-tumor efficacy of a protein (rLZ-8) from Ganoderma lucidum was evaluated, it was demonstrated that rLZ-8 could bind to EGFR specifically, drastically enter into Hepatoma cells, abrogate endosomal recycling and induce HCC cell death. Surprisingly, we screened a monoclonal antibody which possesses competitive binding site with rLZ-8, it also trigger catastrophic EGFR internalization. This result suggests that it is necessary to investigate the interface of EGFR and rLZ-8 complex. An internalization related epitope (S222/K269) was identified on the dimerization arm of EGFR extracellular domain (ECD). These results suggest vulnerability of HCC cells to catastrophic EGFR internalization that can be targeted by a novel epitope and point to the possible exploitation in the design of anti-EGFR therapeutic biologics for HCC therapy.

SUBMITTER: Huang D

PROVIDER: S-EPMC7072198 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy.

Huang Dianshuai D Fan Qingjie Q Liu Zhiyi Z Zhang Shuqin S Huang Wei W Li Hongrui H Liang Chongyang C Sun Fei F

Cancers 20200216 2

The precise role of Epidermal Growth Factor Receptor (EGFR) in Hepatocellular carcinoma (HCC) cells is unknown and EGFR inhibitors have not achieved positive clinical results. The rapid and drastic internalization of EGFR has been proved to successfully treat EGFR inhibitor-resistant patients in recent clinical trials. Here, the anti-tumor efficacy of a protein (rLZ-8) from <i>Ganoderma lucidum</i> was evaluated, it was demonstrated that rLZ-8 could bind to EGFR specifically, drastically enter i ...[more]

PMID: 32079107

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Project description:BackgroundCopper (Cu) and zinc (Zn) are essential nutrients and cofactors of enzymatic reactions with their binding partner. Metallothionein (MT) plays an important role in protecting against heavy metals and oxidative injury, however it may also portend drug resistance and a worse prognosis for hepatocellular carcinoma (HCC) patients. The aim of this study was to determine the amount of Cu, Zn, Cu/Zn and MT in evaluating a group of patients with HCC, including those treated with lenvatinib.MethodsWe enrolled 175 patients with HCC (139 men, 36 women; mean age 71.1 years; hepatitis C virus n = 85, hepatitis B virus n = 19, hepatitis C virus and hepatitis B virus n = 2, non-alcoholic steatohepatitis n = 39, alcohol n = 25, others n = 5; Child-Pugh A n = 141, Child-Pugh B n = 30, Child-Pugh C n = 4; Barcelona clinic liver cancer (BCLC) stage 0 n = 38, stage A n = 56, stage B n = 39, stage C n = 38, stage D n = 4). We evaluated the associations between Cu, Zn and MT. The study outcome was liver cancer-specific survival. Moreover, we treated 12 HCC patients with lenvatinib and investigated the changes in MT during lenvatinib therapy.ResultsThe serum level of Cu was positively correlated with alanine aminotransferase and the BCLC stage. The serum level of Zn decreased concordant with liver disease progression. Patients with a Cu/Zn ratio≥0.999 had significantly improved rates of survival when compared to patients with a Cu/Zn ratio<0.999 (45.3 vs. 30.1 months, p<0.001). MT was significantly correlated with the Cu/Zn ratio and increased after the administration of lenvatinib. Using multivariate Cox regression analyses, it was determined that the Cu/Zn ratio (hazard ratio [HR]: 1.442, p = 0.008), alpha-fetoprotein (HR: 1.000, p<0.001) and BCLC stage (HR: 2.087, p<0.001) were independent predictors of survival.ConclusionsThe Cu/Zn ratio could serve as a useful predictive marker for survival in cases of HCC. MT levels increased in HCC patients receiving lenvatinib therapy, and maybe a predictor of reduced survival.

Project description:Hepatocellular carcinoma (HCC) is one of the world's most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field's potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of in vitro and in vivo cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer.

Dataset Information

An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy.

Publications

An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy.

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