Over the last three decades, the scaffold proteins prohibitins-1 and -2 (PHB1/2) have emerged as key signaling proteins regulating a myriad of signaling pathways in health and diseases. Small molecules targeting PHBs display promising effects against cancers, osteoporosis, inflammatory, cardiac and neurodegenerative diseases. This review provides an updated overview of the various classes of PHB ligands, with an emphasis on their mechanism of action and therapeutic potential. We also describe how these ligands have been used to explore PHB signaling in different physiological and pathological settings.

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Colorectal cancer (CRC) exhibits aberrant activation of Wnt/beta-catenin signaling. Many inhibitors of the Wnt/beta-catenin pathway have been tested for Wnt-dependent cancers including CRC but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or pre-clinical models of intestinal tumorigenesis. In vitro studies suggest that flavaglines target Prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. PHB1 is a highly conserved protein with diverse functions that depend on its post-translational modifications and subcellular localization. Here we demonstrate that FL3 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and ApcMin/+ mouse models and in human CRC tumor organoids (tumoroids) by inhibiting Wnt/beta-catenin signaling via induction of Axin1 expression. FL3 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. FL3 response was diminished in CRC cell lines and human CRC tumoroids harboring a mutation at S45 of beta-catenin. PHB1 deficiency in mice or in human CRC tumoroids abolished FL3-induced expression of Axin1 and drove tumoroid death. In CRC cells, FL3 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. These results suggest that FL3 inhibits Wnt/beta-catenin signaling via PHB1-dependent activation of Axin1. FL3 therefore represents a novel compound that combats Wnt pathway-dependent cancers such as CRC.