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 Karst, A. M. Articles by Li, G. Search for Related Content PubMed PubMed Citation Articles by Karst, A. M. Articles by Li, G.

Role of p53 Up-regulated Modulator of Apoptosis and Phosphorylated Akt in Melanoma Cell Growth, Apoptosis, and Patient Survival

¹ Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada and ² Department of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center, Tampa, Florida

Requests for reprints: Gang Li, Jack Bell Research Centre, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. Phone: 604-875-5826; Fax: 604-875-4497; E-mail: gangli{at}interchange.ubc.ca.

Malignant melanoma is an aggressive and chemoresistant form of skin cancer characterized by rapid metastasis and poor patient prognosis. The development of innovative therapies with improved efficacy is critical to treatment of this disease. Here, we show that aberrant expression of two proteins, p53 up-regulated modulator of apoptosis (PUMA) and phosphorylated Akt (p-Akt), is associated with poor patient survival. Using tissue microarray analysis, we found that patients exhibiting both weak PUMA expression and strong p-Akt expression in their melanoma tumor tissue had significantly worse 5-year survival than patients with either weak PUMA or strong p-Akt expression alone (P < 0.001). Strikingly, no patients exhibiting strong PUMA expression and weak p-Akt expression in primary tumor tissue died within 5 years of diagnosis. We propose a two-pronged therapeutic strategy of (a) boosting PUMA expression and (b) inhibiting Akt phosphorylation in melanoma tumor tissue. Here, we report that a recombinant adenovirus containing human PUMA cDNA (ad-PUMA) efficiently inhibits human melanoma cell survival in vitro, rapidly induces apoptosis, and dramatically suppresses human melanoma tumor growth in a severe combined immunodeficient mouse xenograft model. In melanoma cells strongly expressing p-Akt, we show that Akt/protein kinase B signaling inhibitor-2 (API-2; a small-molecule Akt inhibitor) reduces cell survival in a dose- and time-dependent manner and enhances ad-PUMA-mediated growth inhibition of melanoma cells. Finally, we show that, by combining ad-PUMA and API-2 treatments, human melanoma tumor growth can be inhibited by >80% in vivo compared with controls. Our results suggest that a strategy to correct dysregulated PUMA and p-Akt expression in malignant melanoma may be an effective therapeutic option. (Cancer Res 2006; 66(18): 9221-6)

This article has been cited by other articles:

				K. Shen, V. K. Thomas, M. L. Dustin, and L. C. Kam From the Cover: Micropatterning of costimulatory ligands enhances CD4+ T cell function PNAS, June 3, 2008; 105(22): 7791 - 7796. [Abstract] [Full Text] [PDF]

				J.-S. Diallo, A. Aldejmah, A. F. Mouhim, B. Peant, M. A. Fahmy, I. H. Koumakpayi, K. Sircar, L. R. Begin, A.-M. Mes-Masson, and F. Saad NOXA and PUMA Expression Add to Clinical Markers in Predicting Biochemical Recurrence of Prostate Cancer Patients in a Survival Tree Model Clin. Cancer Res., December 1, 2007; 13(23): 7044 - 7052. [Abstract] [Full Text] [PDF]

				A. R. M. R. Amin, V. S. Thakur, R. K. Paul, G. S. Feng, C.-K. Qu, H. Mukhtar, and M. L. Agarwal SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG PNAS, March 27, 2007; 104(13): 5419 - 5424. [Abstract] [Full Text] [PDF]