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.
Highlights
IntroductionWell-recognized examples are upregulated incorporation of glucose as in aerobic glycolysis or the Warburg effect [3] and that of glutamine [2], as seen in the phenomenon of the accumulation of radioactive fluorine–labeled glucose or glutamine in tumor tissue in a wide variety of cancers [4, 5]
Cancer cells exhibit addiction to a specific metabolism [1, 2]
Well-recognized examples are upregulated incorporation of glucose as in aerobic glycolysis or the Warburg effect [3] and that of glutamine [2], as seen in the phenomenon of the accumulation of radioactive fluorine–labeled glucose or glutamine in tumor tissue in a wide variety of cancers [4, 5]. The metabolism of these 2 principal nutrients contributes to rapid tumor growth and metastasis by producing an array of metabolic intermediates used for the synthesis of cellular building blocks and numerous oncogenes after entering the glycolytic pathway or TCA cycle [6]
Summary
Well-recognized examples are upregulated incorporation of glucose as in aerobic glycolysis or the Warburg effect [3] and that of glutamine [2], as seen in the phenomenon of the accumulation of radioactive fluorine–labeled glucose or glutamine in tumor tissue in a wide variety of cancers [4, 5]. The metabolism of these 2 principal nutrients contributes to rapid tumor growth and metastasis by producing an array of metabolic intermediates used for the synthesis of cellular building blocks and numerous oncogenes after entering the glycolytic pathway or TCA cycle [6]. Pharmacological or genetic impairment of ETCC1 induces a severe metabolic disruption of glycolysis and glutaminolysis and diminishes the tumorigenic and metastatic activities of cancer cells [8,9,10]
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