Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
Department of Sports Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
Endocr Relat Cancer. 2019 Feb;26(2):187-199. doi: 10.1530/ERC-18-0370.
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.
尤文氏肉瘤家族肿瘤 (ESFTs) 是一组侵袭性和高度转移性肿瘤，缺乏有效的治疗方法。胰岛素样生长因子 1 受体 (IGF1R) 阻断是 ESFTs 最有效的靶向治疗之一。然而，由于 IGF1R 阻断诱导的胰岛素受体 (IR) 信号的激活，药物耐药和疾病复发阻碍了其应用。在此，β-榄香烯，一种源自天然植物的化合物，对 ESFT 细胞表现出显著的增殖抑制作用，而 caspase 抑制剂 Z-VAD 则削弱了这种作用。β-榄香烯与 IGF1R 抑制剂联合使用，显著增强了 IGF1R 抑制剂对细胞增殖和 mTOR 激活的抑制作用，并抑制了 IGF1R 抑制剂诱导的 PI3K 磷酸化。为了研究其机制，我们重点研究了β-榄香烯对 IR 信号通路的影响。β-榄香烯显著抑制了胰岛素驱动的肿瘤细胞生长和 mTOR 和 PI3K 的激活，而对正常肝细胞的毒性要低得多。此外，还发现β-榄香烯显著抑制了肿瘤细胞中而非正常肝细胞中 IR 的磷酸化。此外，β-榄香烯在体内抑制了 ESFT 异种移植瘤的生长，并且在β-榄香烯处理的异种移植瘤中，IR 和 S6 核糖体蛋白的磷酸化显著受到抑制。这些数据表明，β-榄香烯通过抑制肿瘤细胞中 IR 的磷酸化来特异性抑制肿瘤细胞的增殖，并增强 IGF1R 抑制剂的作用。因此，本研究为β-榄香烯单独或与 IGF1R 阻断联合应用于 ESFTs 和 IR 信号过度激活肿瘤提供了新的方法学依据。
