The precise molecular mechanism underlying arsenic trioxide (As 2O3)-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 As 2O3 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 (ΔΨm) 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.
|Number of pages||9|
|State||Published - Feb 12 2004|
Bibliographical noteFunding Information:
We are grateful to Professor Y Tsujimoto (Osaka University, Japan) for providing the Bcl-XL expression vector and VDAC antibodies, Dr M Forte (Vollum Institute, Oregon Health Sciences University, Portland, USA) for wild-type and VDAC-deficient yeast strains. We wish to thank Mrs J Wang and Mr XD Liao for their technical assistance in flow cytometry. We would like to thank our colleagues for helpful discussions. This work was supported by grants of ‘One hundred Elite Scholars Project’, ‘Knowledge Innovation Key Project’ of Chinese Academy of Sciences, and the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2002CB513001) awarded to QC and HT, National Outstanding Young Investigator Fellowship of NSFC to HT (30025010), QC and National Institutes of Health (CA81504 and CA82858) to AA.
- Arsenic trioxide
- Bcl-2 proteins
- Cytochrome c
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research