This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zanon, M. Articles by Anichini, A. Search for Related Content PubMed PubMed Citation Articles by Zanon, M. Articles by Anichini, A.

Apoptosis Protease Activator Protein-1 Expression Is Dispensable for Response of Human Melanoma Cells to Distinct Proapoptotic Agents

¹ Human Tumor Immunobiology Unit, Department of Experimental Oncology and ² Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

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 µmol/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 µmol/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.

This article has been cited by other articles:

				K. A. Avery-Kiejda, X. D. Zhang, L. J. Adams, R. J. Scott, B. Vojtesek, D. P. Lane, and P. Hersey Small Molecular Weight Variants of p53 Are Expressed in Human Melanoma Cells and Are Induced by the DNA-Damaging Agent Cisplatin Clin. Cancer Res., March 15, 2008; 14(6): 1659 - 1668. [Abstract] [Full Text] [PDF]

				S. M. Pupa, S. Giuffre, F. Castiglioni, L. Bertola, M. Cantu, I. Bongarzone, P. Baldassari, R. Mortarini, W. S. Argraves, A. Anichini, et al. Regulation of Breast Cancer Response to Chemotherapy by Fibulin-1 Cancer Res., May 1, 2007; 67(9): 4271 - 4277. [Abstract] [Full Text] [PDF]

				S. Chintharlapalli, S. Papineni, S. K. Ramaiah, and S. Safe Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors Cancer Res., March 15, 2007; 67(6): 2816 - 2823. [Abstract] [Full Text] [PDF]

				M. Verhaegen, J. A. Bauer, C. Martin de la Vega, G. Wang, K. G. Wolter, J. C. Brenner, Z. Nikolovska-Coleska, A. Bengtson, R. Nair, J. T. Elder, et al. A Novel BH3 Mimetic Reveals a Mitogen-Activated Protein Kinase-Dependent Mechanism of Melanoma Cell Death Controlled by p53 and Reactive Oxygen Species Cancer Res., December 1, 2006; 66(23): 11348 - 11359. [Abstract] [Full Text] [PDF]

				B. Zhivotovsky and S. Orrenius Carcinogenesis and apoptosis: paradigms and paradoxes Carcinogenesis, October 1, 2006; 27(10): 1939 - 1945. [Abstract] [Full Text] [PDF]

				C. Petti, A. Molla, C. Vegetti, S. Ferrone, A. Anichini, and M. Sensi Coexpression of NRASQ61R and BRAFV600E in Human Melanoma Cells Activates Senescence and Increases Susceptibility to Cell-Mediated Cytotoxicity. Cancer Res., July 1, 2006; 66(13): 6503 - 6511. [Abstract] [Full Text] [PDF]

				X. Wu, K. Takenaka, E. Sonoda, H. Hochegger, S. Kawanishi, T. Kawamoto, S. Takeda, and M. Yamazoe Critical Roles for Polymerase {zeta} in Cellular Tolerance to Nitric Oxide-Induced DNA Damage Cancer Res., January 15, 2006; 66(2): 748 - 754. [Abstract] [Full Text] [PDF]

				Y. Fernandez, M. Verhaegen, T. P. Miller, J. L. Rush, P. Steiner, A. W. Opipari Jr., S. W. Lowe, and M. S. Soengas Differential Regulation of Noxa in Normal Melanocytes and Melanoma Cells by Proteasome Inhibition: Therapeutic Implications Cancer Res., July 15, 2005; 65(14): 6294 - 6304. [Abstract] [Full Text] [PDF]

				R. Mortarini, A. Scarito, D. Nonaka, M. Zanon, I. Bersani, E. Montaldi, E. Pennacchioli, R. Patuzzo, M. Santinami, and A. Anichini Constitutive Expression and Costimulatory Function of LIGHT/TNFSF14 on Human Melanoma Cells and Melanoma-Derived Microvesicles Cancer Res., April 15, 2005; 65(8): 3428 - 3436. [Abstract] [Full Text] [PDF]