期刊
ONCOTARGET
卷 7, 期 31, 页码 50258-50276出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10361
关键词
sponge; small molecule; natural products; lung cancer; insulin growth factor receptor
资金
- Swedish Cancer Society [130550]
- Stockholm Cancer Society [131253, 131102, 11 1213]
- Swedish National Board of Health and Welfare
- Knut och Alice Wallenbergs Stiftelse [2011.0113]
- Stockholm County Council
- Karolinska Institutet
- European Union [KBBE-2010-266033]
In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed antitumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1R beta as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1R beta but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据