Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1

Simple Summary Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in cancer cells and enhances cancer proliferation and chemoresistance. It is therefore considered a potential target for cancer treatment. However, a chemical compound that directly regulates PGRMC1 has not been identified. Here, we showed that the natural active compound in licorice, glycyrrhizin (GL), directly binds to heme-dimerized PGRMC1 to inhibit PGRMC1-mediated EGF receptor (EGFR) activation in cancer cells. Chemical screening using GL derivatives revealed that the glucoside derivative glucoglycyrrhizin (GlucoGL) binds more potently to PGRMC1 and contributes to the suppression of PGRMC1-mediated cancer chemoresistance. This study provides the first evidence of chemical compounds that directly bind to PGRMC1 to inhibit its function, and the findings provide new insights for cancer treatments that target PGRMC1. Abstract Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in various cancer cells and contributes to tumor progression. We have previously shown that PGRMC1 forms a unique heme-stacking functional dimer to enhance EGF receptor (EGFR) activity required for cancer proliferation and chemoresistance, and the dimer dissociates by carbon monoxide to attenuate its biological actions. Here, we determined that glycyrrhizin (GL), which is conventionally used to ameliorate inflammation, specifically binds to heme-dimerized PGRMC1. Binding analyses using isothermal titration calorimetry revealed that some GL derivatives, including its glucoside-derivative (GlucoGL), bind to PGRMC1 potently, whereas its aglycone, glycyrrhetinic acid (GA), does not bind. GL and GlucoGL inhibit the interaction between PGRMC1 and EGFR, thereby suppressing EGFR-mediated signaling required for cancer progression. GL and GlucoGL significantly enhanced EGFR inhibitor erlotinib- or cisplatin (CDDP)-induced cell death in human colon cancer HCT116 cells. In addition, GL derivatives suppressed the intracellular uptake of low-density lipoprotein (LDL) by inhibiting the interaction between PGRMC1 and the LDL receptor (LDLR). Effects on other pathways cannot be excluded. Treatment with GlucoGL and CDDP significantly suppressed tumor growth following xenograft transplantation in mice. Collectively, this study indicates that GL derivatives are novel inhibitors of PGRMC1 that suppress cancer progression, and our findings provide new insights for cancer treatment.