Insulin-like growth factors (IGFs) are strong mitogens for a variety of cancer cells, and their overexpression increases the likelihood of tumor development and the tendency to metastasize. The involvement of IGFs in a range of human malignancies suggests that the molecular analysis of IGF regulation leads to a better understanding of human cancers and possibly a new cancer therapy or prevention. The P.l.'s laboratory has been discovering and analyzing molecular pathways that modulate the functions of IGF2, an IGF that is over expressed in human hepatocellular carcinoma, by using the small molecule called 94G6. The drug-like molecule was originally isolated from a chemical library in the P.l.'s laboratory as an inhibitor of insulin-induced adipogenesis, and subsequent assays showed that 94G6 selectively inhibits the viability and growth of IGF2-overexpressing hepatocellular carcinoma cells at the IC50 of 30 nM. Preliminary experiments in the P.l.'s laboratory suggest that one of the targets of 94G6 is MFP-2, a poorly studied protein with unknown function. The binding of 94G6 to MFP-2 appears to activate transcription factor STAT6 and blocks IGF2 functions by expressing proteins including cellular IGF inhibitor IGFBP-1 and cytokine/insulin suppressor SOCS-3. In this application, we plan to further our analysis of the 94G6 pathway and its related ones by a combination of cell biological, molecular biological, biochemical, and organic chemical experiments. The 94G6 pathway may play a role in the regulation of IGF signals and insulin resistance in human cells, and might reveal a crosstalk among cancer, diabetes, and inflammation. Small organic molecules, whether natural or synthetic, have been utilized for discovering and analyzing disease-linked signaling pathways. 94G6 may become another good example of such small molecules.
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