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

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.

AG-205 Upregulates Enzymes Involved in Cholesterol Biosynthesis and Steroidogenesis in Human Endometrial Cells Independently of PGRMC1 and Related MAPR Proteins

“…Firstly, knocking out PGRMC1 and/or PGRMC2 expression did not alter the ability of AG-205 to induce the formation of large endosomes in CHO-K1 and HeLa cells [16]. Secondly, and through a more direct approach, no binding activity of AG-205 to apo-or heme-dimerized PGRMC1 was observed by isothermal titration calorimetry analysis [17].…”

PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling

“…Since activated PGRMC1 may potentiate the oncogenic signaling of ERα and thereby promote breast cancer progression, it may serve as a therapeutic target. In this context, Kabe et al recently identified glycyrrhizin, a major component in licorice extract with anti-inflammatory and anti-viral effects [ 67 ], as a substance that directly binds PGRMC1 and inhibits some of its functions [ 68 ]. In a human colon cancer cell line, glycyrrhizin inhibited the interaction of PGRMC1 with EGFR, suppressing EGFR signaling and increasing chemosensitivity towards erlotinib and cisplatin [ 68 ].…”

“…In this context, Kabe et al recently identified glycyrrhizin, a major component in licorice extract with anti-inflammatory and anti-viral effects [ 67 ], as a substance that directly binds PGRMC1 and inhibits some of its functions [ 68 ]. In a human colon cancer cell line, glycyrrhizin inhibited the interaction of PGRMC1 with EGFR, suppressing EGFR signaling and increasing chemosensitivity towards erlotinib and cisplatin [ 68 ]. Future studies should investigate the effect of glycyrrhizin on PGRMC1 in the context of breast cancer.…”

Recent Advances in Glycyrrhiza glabra (Licorice)-Containing Herbs Alleviating Radiotherapy- and Chemotherapy-Induced Adverse Reactions in Cancer Treatment

“…Overall, glycyrrhizin has been widely studied for combination chemotherapies involving cisplatin, 5-Fluorouracil, radiation, doxorubicin, paclitaxel, etc. [196][197][198][199][200][201][202][203][204][205][206].…”