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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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 8

Petasin inhibits tumor growth in multiple human xenograft and mouse syngeneic models.

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Petasin inhibits tumor growth in multiple human xenograft and mouse syng...
(A) Experimental protocol, tumor volume, and body weight in the experiments to determine the antiproliferative effect of petasin (PT) in the orthotopic B16F10 syngeneic mouse model (n = 8). Triangles under the x axis indicate the timing of administration (adm). ***P < 0.001, 1-way ANOVA with Tukey’s post hoc test. (B) Representative immunoblots for oncogenes, cell cycle–related proteins, and metabolism-related proteins in the tumor samples from A. A pooled control (PC) was used for normalizing signals in different membranes (full data, Supplemental Figure 7). (C) Heatmap summarizing the protein levels (quantified by densitometry, normalized with the β-actin signals) with bar graphs showing the tumor growth rate of each mouse. *P < 0.05, **P < 0.01, Kruskal-Wallis test. Tumor growth rate = (final tumor volume)/(tumor volume at treatment start). (D) Time-course change in ATF4 (amino acid depletion/unfolded protein response marker) expression in tumor tissues. Mice bearing B16F10 subcutaneous masses received a single injection of PT (50 mg/kg, i.p.) and were euthanized at various time points (0, 0.5, 1, 3, 6, 24, 48, 72 hours; n = 3 per time point). The tumor tissue was immunohistochemically stained with anti-ATF4 antibody to count the number of ATF4-positive cells (representative images for 0- and 60-minute time points; scale bar: 20 μm). Spike in the graph after administration indicates successful drug delivery to the tumor tissues. (E and F) Experimental protocol, tumor volume, and body weight of the experiments designed to determine the antiproliferative effect of PT in the human subcutaneous xenograft model using A2058 (glycolytic, E) and NB-1 (glycolysis-impaired, F) cells (n = 8). SID, once per day. Data are presented as the mean ± SEM (A, E, and F) or SD (D). Triangles under the x axis indicate the timing of administration (adm). **P < 0.01, ***P < 0.001; 2-tailed, unpaired Student’s t test. Vehicle: PBS containing 1% v/v DMSO and 10% v/v high-purity oleic acid.