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Apoptosis protease activator protein-1 expression is dispensable for response of human melanoma cells to distinct proapoptotic agents.
- Source :
-
Cancer research [Cancer Res] 2004 Oct 15; Vol. 64 (20), pp. 7386-94. - Publication Year :
- 2004
-
Abstract
- Loss of expression of the apoptosis protease activator protein-1 (APAF-1) in human melanoma is thought to promote resistance to programmed cell death by preventing caspase-9 activation. However, the role of the APAF-1-dependent pathway in apoptosis activated by cellular stress and/or DNA damage has been recently questioned. We investigated APAF-1 expression in a large panel of human melanomas and assessed cellular response to several proapoptotic agents in tumors expressing or lacking APAF-1 protein. In two melanomas with wild-type p53 but with differential expression of APAF-1, treatment with camptothecin, celecoxib, or an nitric oxide synthase inhibitor (1400W) significantly modulated expression of 36 of 96 genes in an apoptosis-specific cDNA macroarray, but APAF-1 mRNA levels were not induced (in APAF-1(-) cells) nor up-regulated (in APAF-1(+) cells), a finding confirmed at the protein level. Treatment with cisplatin, camptothecin, etoposide, betulinic acid, celecoxib, 1400W, and staurosporine promoted enzymatic activity not only of caspases -2, -8, and -3 but also of caspase-9 in both APAF-1(+) and APAF-1(-) tumor cells. Moreover, drug-induced caspase-9 enzymatic activity could be not only partially but significantly reduced by caspase-2, -3, and -8 -specific inhibitors in both APAF-1(+) and APAF-1(-) tumor cells. In response to 1 to 100 micromol/L of cisplatin, camptothecin, or celecoxib, APAF-1(+) melanomas (n = 12) did not show significantly increased levels of apoptosis compared with APAF-1(-) tumors (n = 7), with the exception of enhanced apoptosis in response to a very high dose (100 micromol/L) of etoposide. These results suggest that the response of human melanoma cells to different proapoptotic agents may be independent of their APAF-1 phenotype.
- Subjects :
- Amidines pharmacology
Apoptosis physiology
Apoptotic Protease-Activating Factor 1
Benzylamines pharmacology
Camptothecin pharmacology
Caspase 9
Caspase Inhibitors
Caspases metabolism
Celecoxib
Cell Line, Tumor
Enzyme Activation
Enzyme Inhibitors pharmacology
Humans
Immunohistochemistry
Melanoma metabolism
Protein Biosynthesis drug effects
Proteins genetics
Pyrazoles
RNA, Messenger biosynthesis
RNA, Messenger genetics
Sulfonamides pharmacology
Antineoplastic Agents pharmacology
Apoptosis drug effects
Melanoma drug therapy
Melanoma pathology
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 64
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 15492260
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-04-1640