title: Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells.
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.
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Zovko
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Metka
authors.initials: M
authors.lastname: Novak
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Hååg
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dimitry
authors.initials: D
authors.lastname: Kovalerchick
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Teresa
authors.initials: T
authors.lastname: Holmlund
authors.affiliation: Science for Life Laboratory, Drug Discovery and Development Platform, Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Färnegårdh
authors.affiliation: Department of Zoology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Micha
authors.initials: M
authors.lastname: Ilan
authors.affiliation: School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Carmeli
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.affiliation: Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Viktorsson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation; D011161:Porifera / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: insulin growth factor receptor; lung cancer; natural products; small molecule; sponge