Cellular bio-energetic metabolism and mitochondria are recognized as potential targets for anticancer agents, due to the numerous relevant peculiarities cancer cells exhibit. Jasmonates are anticancer agents that interact directly with mitochondria. Many types of cancer cells exhibit overexpression of the key glycolytic enzyme, hexokinase, and its excessive binding to mitochondria. These characteristics are considered to play a pivotal role in cancer cell growth rate and survival. The aim of this study was to identify mitochondrial molecular targets of jasmonates. Methods: Binding and detachment of hexokinase from mitochondria were determined by hexokinase immunochemical and activity determinations, surface plasmon resonance analysis and planar lipid bilayer voltage dependent anion channel (VDAC)-activity analysis. Hexokinase expression was modified using hexokinase-overexpressing transfectants and its mitochondrial association. Results:. We report that jasmonates bind to hexokinase and detach it from the mitochondria and its mitochondrial anchor? VDAC. Jasmonate-induced detachment from mitochondria occurs in various types of cancer cells including leukemia and solid tumors. Furthermore, the susceptibility of cancer cells and mitochondria to jasmonates is dependent on the expression of hexokinase, supporting a cause and effect relationship between jasmonate-induced hexokinase detachment and cell death. Conclusions: 1) Our findings provide an explanation for the selective effects of jasmonates on cancer cells. 2) This is the first demonstration of a cytotoxic mechanism based on direct interaction between an anticancer agent and hexokinase. 3) The proposed mechanism can serve to guide development of a novel class of small anticancer compounds that kill cancer cells selectively by inhibiting the hexokinase?VDAC interaction. All

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