Work

Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells

Year: 2016

Type: article

Abstract: // Ana Zovko 1 , Metka Novak 1 , Petra Hååg 1 , Dimitry Kovalerchick 2 , Teresa Holmlund 1 , Katarina Färnegårdh 3 , Micha Ilan 4 , Shmuel Carmeli 2 , Rolf Lewensohn 1 , Kristina Viktorsson 1 1 Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden 2 School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel 3 Science for Life Laboratory, Drug Discovery and Development Platform, Department of Organic Chemistry, Stockholm University, Stockholm, Sweden 4 Department of Zoology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Correspondence to: Kristina Viktorsson, email: [email protected] Ana Zovko, email: [email protected] Keywords: sponge, small molecule, natural products, lung cancer, insulin growth factor receptor Received: June 11, 2015 Accepted: June 15, 2016 Published: July 1, 2016 ABSTRACT In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed anti-tumor 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-1Rβ 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-1Rβ 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.10361