Induction of apoptosis of integrin-expressing human prostate cancer cells by cyclic Arg-Gly-Asp peptides.
Prostate cancer is the second most common cause of cancer deaths among men in the United States. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val; cRGDfV), Arg-Gly-Asp, or Arg-Gly-Asp-Ser, on survival of human prostate cancer (LNCaP and PC-3) and normal (HEL) cells in vitro. Addition of cRGDfV (20 microg/ml) but not the linear Arg-Gly-Asp or Arg-Gly-Asp-Ser peptide induced significant (approximately 84%) killing of LNCaP cells expressing alphavbeta3 integrins on their surfaces. In contrast, none of these peptides had any major effect on the growth of PC-3 or HEL cells, which express little alphavbeta3 integrin on their surfaces. Treatment of LNCaP but not of PC-3 or HEL cells with cRGDfV resulted in cleavage of focal adhesion kinase, a key player in integrin-mediated signal transduction pathway. The evidence we present here suggests that the killing of LNCaP cells after cRGDfV treatment was attributable to apoptosis or programmed cell death. This is evidenced by activation of at least two caspases (caspase-3 and caspase-9) as detected by cleavage of poly(ADP-ribose) polymerase and partial blocking of apoptosis by a selective inhibitor of caspase-9. Our results suggest that cRGDfV may be an effective treatment for some human prostate cancers by inducing apoptosis through interference with the regulation of integrin/focal adhesion kinase-mediated signal transduction pathway necessary for cell survival.
Chatterjee
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JCR Biopharmaceuticals, Inc., 3550 General Atomics Court, San Diego, CA 92121, USA. schat@jcrbio.com
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D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016023:Integrins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D019030:Receptors, Vitronectin; C119707:cyclo(S,S)KYGCRGDWPC; C092113:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl); C047981:arginyl-glycyl-aspartic acid; C046617:arginyl-glycyl-aspartyl-serine; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt