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.
View: Text | PDF
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

×

Figure 10

Petasin inhibits metastasis in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Petasin inhibits metastasis in vivo. (A) Experimental protocol for the e...
(A) Experimental protocol for the experiment designed to determine the inhibitory activity of petasin (PT) against lung colonization of i.v.-injected B16F10 cells. EOD, every other day. (B) Counts and representative images of lung colonies in the mice from A (n = 5; all lung images, Supplemental Figure 15; scale bar: 2.5 mm). (C) Experimental protocol for the experiment used to determine the inhibitory activity of PT against lung and lymph node (LN) metastasis in a spontaneous metastatic model using Jyg-MCB cells. (D) Counts and representative images of lung metastasis in the mice from C (n = 8). The lungs were fixed by infusing neutral buffered 4% paraformaldehyde into the cannulated trachea to visualize the metastatic spots (all lung images, Supplemental Figure 16A; scale bar: 2.5 mm). (E) Representative images of H&E and immunohistochemical staining (p-FAKY397, Ki-67, and p-Histone H3S10) for the lung tissue of mice in C. Scale bar: 50 μm. (F) Percentages of p-FAKY397–positive lung metastatic colonies of mice in C. **P < 0.01, 1-way ANOVA with Fisher’s exact test. (G) Count for Ki-67– or p-Histone H3S10–positive proliferating cells in the lung metastatic tissues (n = 8). (H) Representative images and weight of axillary LNs in C (asterisk, enlarged axillary LNs; arrowheads, primary tumors; scale bar: 3.5 mm). Red dots, weight of enlarged LNs; dashed line, the threshold for LN enlargement. (I) Growth curves for primary subcutaneous Jyg-MCB tumor (n = 8). (J) Body weight of mice in C (n = 8). Vehicle (Veh): PBS containing 1% v/v DMSO and 10% v/v high-purity oleic acid. Triangles under the orange bar in the schematic diagrams indicate the timing of administration (adm). Data are presented as the mean ± SD (B, D, G, and H) or SEM (I and J). *P < 0.05, **P < 0.01, ****P < 0.0001; 2-tailed, unpaired Student’s t test. NS, not significant.