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Science 290 (5493): 989-992

Copyright © 2000 by the American Association for the Advancement of Science

Role of BAX in the Apoptotic Response to Anticancer Agents

Lin Zhang, Jian Yu, Ben Ho Park, Kenneth W. Kinzler, Bert Vogelstein*

To assess the role of BAX in drug-induced apoptosis in human colorectal cancer cells, we generated cells that lack functional BAX genes. Such cells were partially resistant to the apoptotic effects of the chemotherapeutic agent 5-fluorouracil, but apoptosis was not abolished. In contrast, the absence of BAX completely abolished the apoptotic response to the chemopreventive agent sulindac and other nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibited the expression of the antiapoptotic protein Bcl-XL, resulting in an altered ratio of BAX to Bcl-XL and subsequent mitochondria-mediated cell death. These results establish an unambiguous role for BAX in apoptotic processes in human epithelial cancers and may have implications for cancer chemoprevention strategies.

Howard Hughes Medical Institute, Oncology Center, and Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
*   To whom correspondence should be addressed. E-mail: vogelbe{at}welch.jhu.edu


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G. Wu, M. Osada, Z. Guo, A. Fomenkov, S. Begum, M. Zhao, S. Upadhyay, M. Xing, F. Wu, C. Moon, et al. (2005)
Cancer Res. 65, 758-766
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Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer.
Y. Oida, B. Gopalan, R. Miyahara, S. Inoue, C. D. Branch, A. M. Mhashilkar, E. Lin, B. N. Bekele, J. A. Roth, S. Chada, et al. (2005)
Mol. Cancer Ther. 4, 291-304
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Combination of IFN-{alpha} and 5-Fluorouracil Induces Apoptosis through IFN-{alpha}/{beta} Receptor in Human Hepatocellular Carcinoma Cells.
M. Kondo, H. Nagano, H. Wada, B. Damdinsuren, H. Yamamoto, N. Hiraoka, H. Eguchi, A. Miyamoto, T. Yamamoto, H. Ota, et al. (2005)
Clin. Cancer Res. 11, 1277-1286
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Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis.
H. Erdal, M. Berndtsson, J. Castro, U. Brunk, M. C. Shoshan, and S. Linder (2005)
PNAS 102, 192-197
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Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics.
P. WORKMAN (2005)
Cold Spring Harb Symp Quant Biol 70, 499-515
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Inhibition of Cyclooxygenase (COX)-2 Expression by Tet-Inducible COX-2 Antisense cDNA in Hormone-Refractory Prostate Cancer Significantly Slows Tumor Growth and Improves Efficacy of Chemotherapeutic Drugs.
D. S. Dandekar and B. L. Lokeshwar (2004)
Clin. Cancer Res. 10, 8037-8047
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Organ-selective chemoresistance in metastasis from human breast cancer cells: inhibition of apoptosis, genetic variability and microenvironment at the metastatic focus.
B. Gu, L. Espana, O. Mendez, A. Torregrosa, and A. Sierra (2004)
Carcinogenesis 25, 2293-2301
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SMAC/Diablo-dependent apoptosis induced by nonsteroidal antiinflammatory drugs (NSAIDs) in colon cancer cells.
M. Kohli, J. Yu, C. Seaman, A. Bardelli, K. W. Kinzler, B. Vogelstein, C. Lengauer, and L. Zhang (2004)
PNAS 101, 16897-16902
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Inhibition of Extracellular-signal Regulated Kinases 1/2 Is Required for Apoptosis of Human Colon Cancer Cells In vitro by Sulindac Metabolites.
P. L. Rice, K. S. Beard, L. J. Driggers, and D. J. Ahnen (2004)
Cancer Res. 64, 8148-8151
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Hydrogen Peroxide-Mediated Cytosolic Acidification Is a Signal for Mitochondrial Translocation of Bax during Drug-Induced Apoptosis of Tumor Cells.
K. A. Ahmad, K. B. Iskandar, J. L. Hirpara, M.-V. Clement, and S. Pervaiz (2004)
Cancer Res. 64, 7867-7878
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Apoptosis and colorectal cancer.
A J M Watson (2004)
Gut 53, 1701-1709
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Non-steroidal anti-inflammatory drug activated gene (NAG-1) expression is closely related to death receptor-4 and -5 induction, which may explain sulindac sulfide induced gastric cancer cell apoptosis.
T. J. Jang, H. J. Kang, J. R. Kim, and C. H. Yang (2004)
Carcinogenesis 25, 1853-1858
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Ectopic expression of Bcl-XL or Ku70 protects human colon cancer cells (SW480) against curcumin-induced apoptosis while their down-regulation potentiates it.
R. Rashmi, S. Kumar, and D. Karunagaran (2004)
Carcinogenesis 25, 1867-1877
   Abstract »    Full Text »    PDF »
Regulation of Bax Activation and Apoptotic Response to Microtubule-damaging Agents by p53 Transcription-dependent and -independent Pathways.
H. Yamaguchi, J. Chen, K. Bhalla, and H.-G. Wang (2004)
J. Biol. Chem. 279, 39431-39437
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