Sugiyama, Shudo, Hosokawa, Watanabe, Nakano, Kakizuka (2019) Emodin, as a mitochondrial uncoupler, induces strong decreases in ATP levels and proliferation of B16F10 cells, owing to their poor glycolytic reserve Genes to cells : devoted to molecular & cellular mechanisms ()


Many types of cancer cells show a characteristic increase in glycolysis, which is called the "Warburg effect". By screening plant extracts, we identified one that decreases cellular ATP levels and suppresses proliferation of malignant melanoma B16F10 cells, but not of non-cancerous MEF cells. We revealed that its active ingredient is emodin, which showed strong anti-proliferative effects on B16F10 cells both in vitro and in vivo. Moreover, we also found that emodin can function as a mitochondrial uncoupler. Consistently, three known mitochondrial uncouplers also displayed potent antiproliferative effects and preferential cellular ATP reduction in B16F10 cells, but not in MEF cells. These uncouplers provoked comparable mitochondrial uncoupling in both cell types, but they manifested dramatically different cellular effects. Namely, in MEF cells, these uncouplers induced three to five-fold increases in glycolysis from the basal state, and this compensatory activation appeared to be responsible for the maintenance of cellular ATP levels. In contrast, B16F10 cells treated with the uncouplers showed less than a two-fold enhancement of glycolysis, which was not sufficient to compensate for the decrease of ATP production. Together, these results raise the possibility that uncouplers could be effective therapeutic agents specifically for cancer cells with prominent "Warburg effect". This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.