Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment

Junjiro Yoshida,Hiroyuki Inoue,Tomokazu Ohishi,Hiroyuki Osada,Takao Shimizu,Takumi Watanabe,Manabu Takamatsu,Yasumitsu Kondoh,Ihomi Usami,Masakatsu Shibasaki,Hikaru Abe,Masahide Amemiya,Ami Ikeda,Kaori Honda,Manabu Kawada,Tetsuo Noda,Tokuichi Kawaguchi,Yuko Asano,Shingo Dan,Chiharu Sakashita,Gulanbar Amori,Mitsuru Sugawara ,Seigo Ohba ,Raphaël Oriez ,Jun Ueno

doi:10.1016/j.isci.2021.103497

Abstract

The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.

Highlights

Tumor tissues contain cancer cells and several stromal cells, such as macrophages (Hao et al, 2018; Mantovani et al, 2017), vascular endothelial cells (Hida et al, 2004; Huang et al, 2019), immune cells (Lambrechts et al, 2018; Lavin et al, 2017), and fibroblasts (Kalluri, 2016; Mizutani et al, 2019)
SUMMARY The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown
ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s)

Summary

Introduction

Tumor tissues contain cancer cells and several stromal cells, such as macrophages (Hao et al, 2018; Mantovani et al, 2017), vascular endothelial cells (Hida et al, 2004; Huang et al, 2019), immune cells (Lambrechts et al, 2018; Lavin et al, 2017), and fibroblasts (Kalluri, 2016; Mizutani et al, 2019). Among stromal cells in tumor tissues, cancer-associated fibroblasts (CAFs) produce cytokines, growth factors, and various proteins that constitute the extracellular matrix to support the proliferation of cancer cells (Erez et al, 2010; Kawada et al, 2015; Tian et al, 2019; Zhang et al, 2018). Such a tumor-supportive environment is established by these proteins and metabolites from CAFs that are induced by tumor-stromal cell interactions to support the metabolic energy production of cancer cells in response to lower nutrient conditions in the tumor microenvironment (TME). The TME is a target for cancer therapy, and a more detailed understanding of TME modulation could provide effective strategies for tumor suppression

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Discussion

Conclusion