Inhibition of pRb phosphorylation and cell cycle progression by an antennapedia-p16(INK4A) fusion peptide in pancreatic cancer cells.
In this study, we examined whether or not a small peptide derived from p16(INK4A) protein with the antennapedia carrier sequence could inhibit the growth of pancreatic cancer cells through the inhibition of cell cycle progression. Growth inhibition by the p16-derived peptide was observed in a time- and dose-dependent manner in AsPC-1 and BxPC-3 cells (p16-negative and pRb-positive), whereas Saos-2 cells (p16-positive and pRb-negative) showed no inhibitory effect. In AsPC-1 and BxPC-3 cells, the proportion of cells in the G(1) phase markedly increased 48 h after treatment with 20 microM p16-derived peptide. Cell-cycle analysis of Saos-2 cells showed little change during the entire period of treatment. Immunoblot analysis showed inhibition of pRb phosphorylation after treatment of BxPC-3 with 10 microM p16 peptide. Furthermore, the p16 peptide caused a decrease in cyclin A at later times of treatment. These results demonstrate that the p16-derived peptide can inhibit the growth of p16-negative and pRb-positive pancreatic cancer cells by means of G(1) phase cell cycle arrest resulting from the inhibition of pRb phosphorylation. Restoration of p16/pRb tumor-suppressive pathway by re-expression of p16(INK4A) may play a therapeutic role in the treatment of pancreatic cancer.
Fujimoto
K
K
Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, Japan. koji.fujimoto@vanderbilt.edu
Hosotani
R
R
Miyamoto
Y
Y
Doi
R
R
Koshiba
T
T
Otaka
A
A
Fujii
N
N
Beauchamp
R D
RD
Imamura
M
M
D000595:Amino Acid Sequence; D051943:Antennapedia Homeodomain Protein; D019921:Biotinylation; D002352:Carrier Proteins / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000187:drug effects / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004305:Dose-Response Relationship, Drug; D018398:Homeodomain Proteins / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D051943:Antennapedia Homeodomain Protein; D002352:Carrier Proteins; D019925:Cyclin A; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors