Methyl jasmonate binds to and detaches mitochondria-bound hexokinase

被引:172
作者
Goldin, N. [1 ]
Arzoine, L. [2 ]
Heyfets, A. [1 ]
Israelson, A. [2 ]
Zaslavsky, Z. [3 ]
Bravman, T. [4 ]
Bronner, V. [4 ]
Notcovich, A. [4 ]
Shoshan-Barmatz, V. [2 ]
Flescher, E. [1 ]
机构
[1] Tel Aviv Univ, Sackler Fac Med, Dept Human Microbiol, IL-69978 Tel Aviv, Israel
[2] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel
[3] Tel Aviv Univ, Sackler Fac Med, Interdept Core Facil, IL-69978 Tel Aviv, Israel
[4] Bio Rad Haifa, Haifa, Israel
关键词
jasmonate; target; hexokinase; VDAC; mitochondria;
D O I
10.1038/onc.2008.108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. The aim of this study was to identify mitochondrial molecular targets of jasmonates. We report that jasmonates bind to hexokinase and detach it from the mitochondria and its mitochondrial anchor-the voltage-dependent anion channel (VDAC), as judged by hexokinase immunochemical and activity determinations, surface plasmon resonance analysis and planar lipid bilayer VDAC- activity analysis. Furthermore, the susceptibility of cancer cells and mitochondria to jasmonates is dependent on the expression of hexokinase, evaluated using hexokinase-overexpressing transfect ants and its mitochondrial association. 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. Thus, our findings provide an explanation for the selective effects of jasmonates on cancer cells. Most importantly, this is the first demonstration of a cytotoxic mechanism based on direct interaction between an anticancer agent and hexokinase. The proposed mechanism can serve to guide development of a new selective approach for cancer therapy.
引用
收藏
页码:4636 / 4643
页数:8
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