Role of BAX in the apoptotic response to anticancer agents.

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.

[1]  M. Hull,et al.  The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. , 2000, European journal of cancer.

[2]  Johnson Sc,et al.  Advances in HIV/AIDS therapy. , 2000 .

[3]  H. Ngan,et al.  Changes in p21WAF1, pRb, Mdm-2, Bax and Bcl-2 expression in cervical cancer cell lines transfected with a p53 expressing adenovirus. , 2000, European journal of cancer.

[4]  S. Korsmeyer,et al.  Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null mice: investigations of the mechanistic determinants of epithelial apoptosis in vivo , 1999, Oncogene.

[5]  Matthew G. Vander Heiden,et al.  Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? , 1999, Nature Cell Biology.

[6]  A. de la Chapelle,et al.  Genetic susceptibility to non-polyposis colorectal cancer , 1999, Journal of medical genetics.

[7]  K. Kinzler,et al.  PPARδ Is an APC-Regulated Target of Nonsteroidal Anti-Inflammatory Drugs , 1999, Cell.

[8]  R. DuBois,et al.  The Role of COX‐2 in Intestinal Cancer , 1999, Expert opinion on investigational drugs.

[9]  R. Gaynor,et al.  Sulindac Inhibits Activation of the NF-κB Pathway* , 1999, The Journal of Biological Chemistry.

[10]  S. Korsmeyer,et al.  The activity of the murine Bax promoter is regulated by Sp1/3 and E-box binding proteins but not by p53 , 1999, Cell Death and Differentiation.

[11]  K. Kinzler,et al.  Disruption of p53 in human cancer cells alters the responses to therapeutic agents. , 1999, The Journal of clinical investigation.

[12]  S. Korsmeyer,et al.  BCL-2 family members and the mitochondria in apoptosis. , 1999, Genes & development.

[13]  S. Korsmeyer,et al.  Inhibition of virus-induced neuronal apoptosis by Bax , 1999, Nature Medicine.

[14]  K. Kinzler,et al.  Requirement for p53 and p21 to sustain G2 arrest after DNA damage. , 1998, Science.

[15]  J C Reed,et al.  Mitochondria and apoptosis. , 1998, Science.

[16]  S. Korsmeyer,et al.  Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis , 1998, The EMBO journal.

[17]  C. Coopersmith,et al.  γ-Ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53 , 1997, Oncogene.

[18]  S. Korsmeyer,et al.  bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J C Reed,et al.  Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator Phenotype , 1997, Science.

[20]  Bert Vogelstein,et al.  Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21 , 1996, Nature.

[21]  S. Korsmeyer,et al.  Bax-Deficient Mice with Lymphoid Hyperplasia and Male Germ Cell Death , 1995, Science.

[22]  Darryl Shibata,et al.  Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis , 1993, Nature.