Petasin potently inhibits mitochondrial complex I–based metabolism that supports tumor growth and metastasis
Kazuki Heishima, … , Hiroshi Ueda, Yukihiro Akao
Kazuki Heishima, … , Hiroshi Ueda, Yukihiro Akao
Published September 1, 2021
Citation Information: J Clin Invest. 2021;131(17):e139933. https://doi.org/10.1172/JCI139933.
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Research Article Metabolism Oncology

Petasin potently inhibits mitochondrial complex I–based metabolism that supports tumor growth and metastasis

Abstract

Mitochondrial electron transport chain complex I (ETCC1) is the essential core of cancer metabolism, yet potent ETCC1 inhibitors capable of safely suppressing tumor growth and metastasis in vivo are limited. From a plant extract screening, we identified petasin (PT) as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo. Despite its higher potency, it showed no apparent toxicity toward nontumor cells and normal organs. Also, treatment with PT attenuated cellular motility and focal adhesion in vitro as well as lung metastasis in vivo. Metabolome and proteome analyses revealed that PT severely depleted the level of aspartate, disrupted tumor-associated metabolism of nucleotide synthesis and glycosylation, and downregulated major oncoproteins associated with proliferation and metastasis. These findings indicate the promising potential of PT as a potent ETCC1 inhibitor to target the metabolic vulnerability of tumor cells.

Authors

Kazuki Heishima, Nobuhiko Sugito, Tomoyoshi Soga, Masashi Nishikawa, Yuko Ito, Ryo Honda, Yuki Kuranaga, Hiroki Sakai, Ryo Ito, Takayuki Nakagawa, Hiroshi Ueda, Yukihiro Akao

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Figure 6

Petasin upregulates ER stress/unfolded protein response signals.

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Petasin upregulates ER stress/unfolded protein response signals. (A) Gen...
(A) Genes and pathways significantly different between tumor (A2058) and nontumor (ASF 4-1) cells treated for 8 hours with PT (3 μM). Most of the differentially expressed genes (DEGs) were ATF4-target genes (marked as red). Metascape was used for the enrichment analysis to determine significantly different pathways (KEGG/Reactome pathways; FDR ≤ 0.01). (B) Schematic diagram illustrating ATF4-mediated signals in response to the unfolded protein/ER stress and amino acid depletion. (C) Time-course change in ATF4 expression in B16F10 or A2058 cells treated with PT (3 μM) or DMSO (loading control, β-actin). The data were obtained from the same membrane for comparison between different durations of treatment (intact images, Supplemental Figure 5). (D) Time-course changes in ATF4-regulated genes in B16F10 cells treated with PT (3 μM). (E) Differential expression of ATF4-regulated metabolic enzymes in A2058 and ASF 4-1 cells treated with PT (3 μM). (F) Integrated pathway map illustrating metabolites and transcripts altered by PT treatment (3 μM). Altered metabolites are illustrated with colors (red, high in tumor cells; blue, low in tumor cells) and size of circles (degree of difference between tumor and nontumor cells). Enzyme names are colored depending on their properties (orange, ATF4-regulated metabolic enzymes; green, NAD-consuming enzymes). (G and H) DEGs (G) and their Circos plot (H) for A2058 cells treated for 8 hours with PT (3 μM), metformin (Met, 5000 μM), or phenformin (Phen, 50 μM). The Circos plot illustrates DEG overlap between cells treated with each agent. The heatmaps were illustrated by cluster analysis (Ward’s method). DEGs were defined as follows: absolute log2 fold changes ≥ 1 for A or 0.585 for G, P values ≤ 0.05; 2-tailed, paired Student’s t test (n = 3).