Resumen
The correct folding of proteins is essential for their activity. Therefore, cells have evolved protein-folding chaperones, such as Hsp90. Interestingly, in several cancer cells, Hsp90 appears to have a role that is more important than normal. The current working model suggests that, with the help of its co-chaperone, Cdc37, it stabilizes mutant kinases. However, Hsp90, together with Cdc37, assists additional proteins that may be relevant in cancer. We demonstrate that the Hsp90-dependent stability of the transcription factor HIF-1a and one of its downstream transcriptional targets, galectin-3, is important to maintain the elevated activity of the major oncogene KRAS. This is because galectin-3 stabilizes the MAPK-signaling complexes of K-Ras, which is called a nanocluster. In addition, we identified six drug-like small molecules that inhibit the Hsp90/Cdc37 protein interface at low micro molar concentrations. Given the co-occurrence of mutant KRAS with high HIF-1a and high galectin-3 levels in pancreatic cancer, our results suggest an application of Hsp90 inhibitors in this cancer type.