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Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor

Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease...

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Autores principales: Wu, Dawei, Lv, Dongwei, Zhang, Ting, Guo, Lianying, Ma, Fangli, Zhang, Caihua, Lv, Guofeng, Huang, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347285/
https://www.ncbi.nlm.nih.gov/pubmed/30422809
http://dx.doi.org/10.1530/ERC-18-0370
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author Wu, Dawei
Lv, Dongwei
Zhang, Ting
Guo, Lianying
Ma, Fangli
Zhang, Caihua
Lv, Guofeng
Huang, Lin
author_facet Wu, Dawei
Lv, Dongwei
Zhang, Ting
Guo, Lianying
Ma, Fangli
Zhang, Caihua
Lv, Guofeng
Huang, Lin
author_sort Wu, Dawei
collection PubMed
description Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein β-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. β-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of β-elemene on IR signaling pathway. β-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by β-elemene specifically in tumor cells other than normal hepatocytes. In addition, β-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the β-elemene-treated xenografts. These data suggest that β-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by β-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.
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spelling pubmed-63472852019-01-29 Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor Wu, Dawei Lv, Dongwei Zhang, Ting Guo, Lianying Ma, Fangli Zhang, Caihua Lv, Guofeng Huang, Lin Endocr Relat Cancer Research Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein β-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. β-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of β-elemene on IR signaling pathway. β-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by β-elemene specifically in tumor cells other than normal hepatocytes. In addition, β-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the β-elemene-treated xenografts. These data suggest that β-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by β-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors. Bioscientifica Ltd 2018-11-12 /pmc/articles/PMC6347285/ /pubmed/30422809 http://dx.doi.org/10.1530/ERC-18-0370 Text en © 2019 The authors http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Wu, Dawei
Lv, Dongwei
Zhang, Ting
Guo, Lianying
Ma, Fangli
Zhang, Caihua
Lv, Guofeng
Huang, Lin
Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
title Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
title_full Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
title_fullStr Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
title_full_unstemmed Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
title_short Antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
title_sort antitumor effects of β-elemene via targeting the phosphorylation of insulin receptor
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347285/
https://www.ncbi.nlm.nih.gov/pubmed/30422809
http://dx.doi.org/10.1530/ERC-18-0370
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