Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch.
Pyruvate is situated at the intersection of oxidative phosphorylation (OXPHOS) and glycolysis, which are the primary energy-producing pathways in cells. Cancer therapies targeting these pathways have been previously documented, indicating that inhibiting one pathway may lead to functional compensati...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0309700 |
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| author | Yuki Aisu Nobu Oshima Fuminori Hyodo Abdelazim Elsayed Elhelaly Akihiko Masuo Tomoaki Okada Shigeo Hisamori Shigeru Tsunoda Koya Hida Tomonori Morimoto Hiroyuki Miyoshi Makoto M Taketo Masayuki Matsuo Leonard M Neckers Yoshiharu Sakai Kazutaka Obama |
| author_facet | Yuki Aisu Nobu Oshima Fuminori Hyodo Abdelazim Elsayed Elhelaly Akihiko Masuo Tomoaki Okada Shigeo Hisamori Shigeru Tsunoda Koya Hida Tomonori Morimoto Hiroyuki Miyoshi Makoto M Taketo Masayuki Matsuo Leonard M Neckers Yoshiharu Sakai Kazutaka Obama |
| author_sort | Yuki Aisu |
| collection | DOAJ |
| description | Pyruvate is situated at the intersection of oxidative phosphorylation (OXPHOS) and glycolysis, which are the primary energy-producing pathways in cells. Cancer therapies targeting these pathways have been previously documented, indicating that inhibiting one pathway may lead to functional compensation by the other, resulting in an insufficient antitumor effect. Thus, effective cancer treatment necessitates concurrent and comprehensive suppression of both. However, whether a metabolic switch between the metabolic pathways occurs in colorectal and gastric cancer cells and whether blocking it by inhibiting both pathways has an antitumor effect remain to be determined. In the present study, we used two small molecules, namely OXPHOS and glycolysis inhibitors, to target pyruvate metabolic pathways as a cancer treatment in these cancer cells. OXPHOS and glycolysis inhibition each augmented the other metabolic pathway in vitro and in vivo. OXPHOS inhibition alone enhanced glycolysis and showed antitumor effects on colorectal and gastric cancer cells in vitro and in vivo. Moreover, glycolysis inhibition in addition to OXPHOS inhibition blocked the metabolic switch from OXPHOS to glycolysis, causing an energy depletion and deterioration of the tumor microenvironment that synergistically enhanced the antitumor effect of OXPHOS inhibitors. In addition, using hyperpolarized 13C-magnetic resonance spectroscopic imaging (HP-MRSI), which enables real-time and in vivo monitoring of molecules containing 13C, we visualized how the inhibitors shifted the flux of pyruvate and how this dual inhibition in colorectal and gastric cancer mouse models altered the two pathways. Integrating dual inhibition of OXPHOS and glycolysis with HP-MRSI, this therapeutic model shows promise as a future "cancer theranostics" treatment option. |
| format | Article |
| id | doaj-art-e6f1c773e575447aaf8ece3fe500cb4a |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-e6f1c773e575447aaf8ece3fe500cb4a2024-12-17T05:31:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-011912e030970010.1371/journal.pone.0309700Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch.Yuki AisuNobu OshimaFuminori HyodoAbdelazim Elsayed ElhelalyAkihiko MasuoTomoaki OkadaShigeo HisamoriShigeru TsunodaKoya HidaTomonori MorimotoHiroyuki MiyoshiMakoto M TaketoMasayuki MatsuoLeonard M NeckersYoshiharu SakaiKazutaka ObamaPyruvate is situated at the intersection of oxidative phosphorylation (OXPHOS) and glycolysis, which are the primary energy-producing pathways in cells. Cancer therapies targeting these pathways have been previously documented, indicating that inhibiting one pathway may lead to functional compensation by the other, resulting in an insufficient antitumor effect. Thus, effective cancer treatment necessitates concurrent and comprehensive suppression of both. However, whether a metabolic switch between the metabolic pathways occurs in colorectal and gastric cancer cells and whether blocking it by inhibiting both pathways has an antitumor effect remain to be determined. In the present study, we used two small molecules, namely OXPHOS and glycolysis inhibitors, to target pyruvate metabolic pathways as a cancer treatment in these cancer cells. OXPHOS and glycolysis inhibition each augmented the other metabolic pathway in vitro and in vivo. OXPHOS inhibition alone enhanced glycolysis and showed antitumor effects on colorectal and gastric cancer cells in vitro and in vivo. Moreover, glycolysis inhibition in addition to OXPHOS inhibition blocked the metabolic switch from OXPHOS to glycolysis, causing an energy depletion and deterioration of the tumor microenvironment that synergistically enhanced the antitumor effect of OXPHOS inhibitors. In addition, using hyperpolarized 13C-magnetic resonance spectroscopic imaging (HP-MRSI), which enables real-time and in vivo monitoring of molecules containing 13C, we visualized how the inhibitors shifted the flux of pyruvate and how this dual inhibition in colorectal and gastric cancer mouse models altered the two pathways. Integrating dual inhibition of OXPHOS and glycolysis with HP-MRSI, this therapeutic model shows promise as a future "cancer theranostics" treatment option.https://doi.org/10.1371/journal.pone.0309700 |
| spellingShingle | Yuki Aisu Nobu Oshima Fuminori Hyodo Abdelazim Elsayed Elhelaly Akihiko Masuo Tomoaki Okada Shigeo Hisamori Shigeru Tsunoda Koya Hida Tomonori Morimoto Hiroyuki Miyoshi Makoto M Taketo Masayuki Matsuo Leonard M Neckers Yoshiharu Sakai Kazutaka Obama Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch. PLoS ONE |
| title | Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch. |
| title_full | Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch. |
| title_fullStr | Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch. |
| title_full_unstemmed | Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch. |
| title_short | Dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch. |
| title_sort | dual inhibition of oxidative phosphorylation and glycolysis exerts a synergistic antitumor effect on colorectal and gastric cancer by creating energy depletion and preventing metabolic switch |
| url | https://doi.org/10.1371/journal.pone.0309700 |
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