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 4

Petasin disrupts tumor-associated metabolism.

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Petasin disrupts tumor-associated metabolism. (A and B) Pathway maps ill...
(A and B) Pathway maps illustrating significantly different metabolites between tumor (B16F10) and nontumor (ASF 4-1) cells treated for 9 (A) or 48 (B) hours with petasin (PT, 3 μM) or DMSO. 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; abs log2 FC, absolute log2 fold changes). NAD-consuming enzymes are marked as green. The bar graph in the map shows the glucose concentration in the medium of B16F10 cultures treated with 3 μM PT or DMSO for 9 or 48 hours. **P < 0.01, NS (not significant); 2-tailed, unpaired Student’s t test (n = 3). (C) Cluster analysis (Ward’s method) and heatmap showing significantly different metabolites in B16F10 and ASF 4-1 cells treated for 9 or 48 hours with PT (3 μM) or DMSO. (D) Cell viability percentages of B16F10 cells treated for 48 hours with PT alone (0.3 μM) or PT (0.3 μM) and aspartate (Asp, 10 mM). EMEM was used for the assay. ***P < 0.001, 1-way ANOVA with Tukey’s post hoc test. Metabolites with abs log2 FC greater than 0.585 and P values of less than 0.05 were included in the pathway map and heatmap. These assays were performed with high-glucose DMEM supplemented with 10% FBS unless otherwise indicated. Data are presented as the mean ± SD (n = 3).