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.