Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death

被引：126

作者：

Rimmerman, N. ^{[1
]}

Ben-Hail, D. ^{[2
,3
]}

Porat, Z. ^{[4
]}

Juknat, A. ^{[1
]}

Kozela, E. ^{[1
]}

Daniels, M. P. ^{[5
]}

Connelly, P. S. ^{[5
]}

Leishman, E. ^{[6
]}

Bradshaw, H. B. ^{[6
]}

Shoshan-Barmatz, V. ^{[2
,3
]}

Vogel, Z. ^{[1
]}

机构：

[1] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, Dr Miriam & Sheldon G Adelson Ctr Biol Addict Dis, IL-6997801 Tel Aviv, Israel

[2] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel

[3] Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, IL-84105 Beer Sheva, Israel

[4] Weizmann Inst Sci, Flow Cytometry Unit, IL-76100 Rehovot, Israel

[5] NHLBI, Bethesda, MD 20892 USA

[6] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA

来源：

CELL DEATH & DISEASE | 2013年 / 4卷

关键词：

cancer; cannabidiol; cell death; microglia; mitochondria; voltage-dependent anion channel 1; INDUCED APOPTOSIS; PERMEABILITY TRANSITION; OXIDATIVE STRESS; ACTIVATION; EXPRESSION; PROTEIN; TRANSLOCATION; CHOLESTEROL; PATHWAYS; BINDING;

D O I：

10.1038/cddis.2013.471

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.

引用

页码：e949 / e949

页数：11

共 60 条

[1] The expression level of the voltage-dependent anion channel controls life and death of the cell [J].