Cutting Off H+ Leaks on the Inner Mitochondrial Membrane: A Proton Modulation Approach to Selectively Eradicate Cancer Stem Cells

Minsu Park, Kyoung Sunwoo, Yoon Jae Kim, Miae Won, Yunjie Xu, Jaewon Kim, Zhongji Pu, Mingle Li, Ji Young Kim, Jae Hong Seo, Jong Seung Kim

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.

Original languageEnglish
Pages (from-to)4647-4658
Number of pages12
JournalJournal of the American Chemical Society
Volume145
Issue number8
DOIs
Publication statusPublished - 2023 Mar 1

Bibliographical note

Funding Information:
The authors gratefully acknowledge the Creative Research Initiatives project (Grant No. 2018R1A3B1052702, J.S.K.) and the Brain Pool Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (Grant No. 2020H1D3A1A02080172, M.L.). This research was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HR20C0021, J.H.S.), and MSIT (Grant No. 2018R1A2B6005347, J.Y.K. and Grant No. 2019M3E5D1A01068998, J.S.K.). The authors also gratefully thank the support from the National Natural Science Foundation of China (Grant No. 82203050, Y.X.).

Publisher Copyright:
© 2023 American Chemical Society.

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

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