In vitro and in vivo tumor growth inhibition by a p16-mimicking peptide in p16INK4A-defective, pRb-positive human melanoma cells.
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.
Noonan
Douglas M
DM
Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy.
Severino
Anna
A
Morini
Monica
M
Tritarelli
Alessandra
A
Manente
Lucrezia
L
D'Agnano
Igea
I
Starace
Giuseppe
G
Baldi
Alfonso
A
Lombardi
Daniela
D
Albini
Adriana
A
Felsani
Armando
A
Paggi
Marco G
MG
D000595:Amino Acid Sequence; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010455:Peptides; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53