In vitro and in vivo tumor growth inhibition by a p16-mimicking peptide in p16INK4A-defective, pRb-positive human melanoma cells.

Abstract

The cell cycle regulatory pathway responsible for the control of the late-G1 checkpoint is found recurrently altered in human malignant melanoma, often due to lack of functional p16 or pRb (pRb-1) proteins. Here we examined the ability of p16-derived peptides to mimic p16 function in two exemplary human melanoma cell lines: the p16-defective, pRb-positive A375M cells and p16-positive, pRb-defective A2058 cells. The synthetic p16-mimicking peptides strongly induced apoptosis in p16-, pRb+ A375M cells in vitro, while they had significantly less activity on p16+, pRb- A2058 cells. The most active p16-mimicking peptide, p16-AP9, also potently inhibited in vivo growth of the A375M melanoma. Treated tumors showed a threefold smaller volume (P < 0.025) and a significant reduction of the mitotic index and of PCNA expression. Growth of A2058 cells in vivo was not affected by treatment with the p16-mimicking peptide. Our results demonstrate that p16-mimicking peptides can induce apoptosis in vitro and that can inhibit tumor growth in vivo in p16-defective, pRb-expressing human melanoma cells, suggesting that p16-mimicking peptides can represent a promising tool for targeted therapy in selected cancer phenotypes.

• Authors: Douglas M Noonan, Anna Severino, Monica Morini, Alessandra Tritarelli, Lucrezia Manente, Igea D'Agnano, Giuseppe Starace, Alfonso Baldi, Daniela Lombardi, Adriana Albini, Armando Felsani, Marco G Paggi
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 202 Issue 3 Pg. 922-8 (Mar 2005) ISSN: 0021-9541 [Print] United States
• PMID: 15389561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2004 Wiley-Liss, Inc.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Peptides
• Retinoblastoma Protein
• Tumor Suppressor Protein p53

Topics

• Amino Acid Sequence
• Apoptosis
• Cell Cycle (physiology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Down-Regulation
• Humans
• Melanoma (metabolism)
• Molecular Sequence Data
• Neoplasms (metabolism)
• Peptides (genetics, metabolism)
• Phosphorylation
• Retinoblastoma Protein (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)