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

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.

• Authors: Junjiro Yoshida, Tomokazu Ohishi, Hikaru Abe, Shun-Ichi Ohba, Hiroyuki Inoue, Ihomi Usami, Masahide Amemiya, Raphael Oriez, Chiharu Sakashita, Shingo Dan, Minoru Sugawara, Tokuichi Kawaguchi, Junko Ueno, Yuko Asano, Ami Ikeda, Manabu Takamatsu, Gulanbar Amori, Yasumitsu Kondoh, Kaori Honda, Hiroyuki Osada, Tetsuo Noda, Takumi Watanabe, Takao Shimizu, Masakatsu Shibasaki, Manabu Kawada
• Journal: iScience (iScience) Vol. 24 Issue 12 Pg. 103497 (Dec 17 2021) ISSN: 2589-0042 [Electronic] United States
• PMID: 34934919 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s).