Glycyrrhizin derivatives suppress cancer chemoresistance by inhibiting progesterone receptor membrane component 1

Yasuaki Kabe, Ikko Koike, Tatsuya Yamamoto, Miwa Hirai, Ayaka Kanai, Ryogo Furuhata, Hitoshi Tsugawa, Erisa Harada, Kenji Sugase, Kazue Hanadate, Nobuji Yoshikawa, Hiroaki Hayashi, Masanori Noda, Susumu Uchiyama, Hiroki Yamazaki, Hirotoshi Tanaka, Takuya Kobayashi, Hiroshi Handa, Makoto Suematsu

研究成果: Article査読

1 被引用数 (Scopus)

抄録

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-deriva-tive (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 pro-vide new insights for cancer treatment.

本文言語English
論文番号3265
ジャーナルCancers
13
13
DOI
出版ステータスPublished - 2021 7 1

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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