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Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells
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Number of Authors: 10
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 31, 50258-50276 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 7, no 31, 50258-50276 p.
Keyword [en]
sponge, small molecule, natural products, lung cancer, insulin growth factor receptor
National Category
Cell Biology Cell and Molecular Biology
URN: urn:nbn:se:su:diva-135981DOI: 10.18632/oncotarget.10361ISI: 000385422000110OAI: diva2:1050364
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2016-11-28Bibliographically approved

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Färnegårdh, Katarina
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Department of Organic ChemistryScience for Life Laboratory (SciLifeLab)
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