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- Title
Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide.
- Authors
Yanhua Zheng, George Q.; Yong Shi; Changhai Tian, George Q.; Chunsun Jiang, George Q.; Haijing Jin, George Q.; Jianjun Chen; Hong Tang; Quan Chen; Alex Almasan, George Q.
- Abstract
The precise molecular mechanism underlying arsenic trioxide (As2O3)-induced apoptosis is a subject of extensive study. Here, we show that clinically relevant doses of As2O3 can induce typical apoptosis in IM-9, a multiple myeloma cell line, in a Bcl-2 inhibitable manner. We confirmed that As2O3 directly induced cytochrome c (cyto c) release from isolated mouse liver mitochondria via the mitochondrial permeability transition pore, and we further identified the voltage-dependent anion channel (VDAC) as a biological target of As2O3 responsible for eliciting cyto c release in apoptosis. First, pretreatment of the isolated mitochondria with an anti-VDAC antibody specifically prevented As2O3-induced cyto c release. Second, in proteoliposome experiments, VDAC by itself was sufficient to mediate As2O3-induced cyto c release, which could be specifically inhibited by Bcl-XL. Third, As2O3 induced mitochondria membrane potential (??m) reduction and cyto c release only in the VDAC-expressing, but not in the VDAC-deficient yeast strain. Finally, we found that As2O3 induced the increased expression and homodimerization of VDAC in IM-9 cells, but not in Bcl-2 overexpressing cells, suggesting that VDAC homodimerization could potentially determine its gating capacity to cyto c, and Bcl-2 blockage of VDAC homodimerization represents a novel mechanism for its inhibition of apoptosis.Oncogene (2004) 23, 1239-1247. doi:10.1038/sj.onc.1207205 Published online 1 December 2003
- Subjects
ION channels; ARSENIC; APOPTOSIS; CYTOCHROME c; MITOCHONDRIA; YEAST
- Publication
Oncogene, 2004, Vol 23, Issue 6, p1239
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1207205