Oncotarget

Research Papers:

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

Ana Zovko, Metka Novak, Petra Hååg, Dimitry Kovalerchick, Teresa Holmlund, Katarina Färnegårdh, Micha Ilan, Shmuel Carmeli, Rolf Lewensohn and Kristina Viktorsson _

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Oncotarget. 2016; 7:50258-50276. https://doi.org/10.18632/oncotarget.10361

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Abstract

Ana Zovko1, Metka Novak1, Petra Hååg1, Dimitry Kovalerchick2, Teresa Holmlund1, Katarina Färnegårdh3, Micha Ilan4, Shmuel Carmeli2, Rolf Lewensohn1, Kristina Viktorsson1

1Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden

2School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel

3Science for Life Laboratory, Drug Discovery and Development Platform, Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

4Department of Zoology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

Correspondence to:

Kristina Viktorsson, email: kristina.viktorsson@ki.se

Ana Zovko, email: zovko.ana@gmail.com

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.


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