Enhancing the apoptotic potential of insulin-like growth factor-binding protein-3 in prostate cancer by modulation of CK2 phosphorylation.
IGF-binding protein 3 (IGFBP-3) promotes apoptosis by both IGF-dependent and -independent mechanisms. We have previously reported that phosphorylation of IGFBP-3 (S156) by DNA-dependent protein kinase enhances its nuclear accumulation and is essential for its ability to interact with retinoid X receptor-alpha and induce apoptosis in cultured prostate cancer cells. Using specific chemical inhibitors and small interfering RNA, we demonstrate that preventing casein kinase 2 (CK2) activation enhanced the apoptotic potential of IGFBP-3. We mapped potential CK2 phosphosphorylation sites in IGFBP-3 to S167 and S175 and identified that wild-type IGFBP-3- and IGFBP-3-S175A-induced apoptosis to a comparable extent. In contrast, IGFBP-3-S167A was far more potently apoptosis inducing due to inability to undergo CK2 phosphorylation. Pretreatment of 22RV1 cells with IGFBP-3 small interfering RNA also limits the ability of high doses of CK2 inhibitor to induce apoptosis. These effects can be reversed by the addition of exogenous IGFBP-3 protein, suggesting reciprocal regulation of cell survival and apoptosis by IGFBP-3 and CK2. These studies reveal multisite phosphorylation of IGFBP-3 that both positively and negatively regulate its apoptotic potential. Understanding such intrinsic regulation of IGFBP-3 action may enhance the development of potential cancer therapies.
Cobb
Laura J
LJ
Division of Pediatric Endocrinology, Mattel Children's Hospital at University of California, Los Angeles, California, USA.
Mehta
Hemal
H
Cohen
Pinchas
P
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000737:chemistry / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D021381:Protein Transport
D018972:Insulin-Like Growth Factor Binding Protein 3; D009687:Nuclear Proteins; D010768:Phosphoserine; D047390:Casein Kinase II; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D048031:JNK Mitogen-Activated Protein Kinases