title: Hormonal regulation of IGFBP-2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model.
abstract: The identification of molecular determinants involved in the promotion of metastasis and development of androgen insensitive prostate cancer (AI-PCa) is necessary to discriminate aggressive from indolent disease and to identify therapeutic targets for advanced disease. Overexpression of one particular member of the insulin like growth factor (IGF) axis, IGFBP-2, is implicated in the development of AI-PCa and other cancers. Using the LNCaP human PCa progression model, we show that the AI and metastatic prostate cancer cell line C4-2B4 expresses greater amounts of secreted IGFBP-2 than the androgen sensitive (AS), non-metastatic LNCaP progenitor cell line. Further, the ability of androgens to decrease extracellular IGFBP-2 levels is attenuated in the AI and metastatic C4-2 cell line. The ability of androgen to negatively regulate extracellular IGFBP-2 levels was blocked by Casodex in a dose-dependent manner. The mechanism underlying the androgen-induced downregulation of secreted IGFBP-2 appears to involve extracellular proteolysis, resulting in the production of IGFBP-2 fragments lacking the ability to bind IGF-I and IGF-II. As C4-2 cells have an attenuated ability to proteolyze IGFBP-2 in response to androgen and C4-2B4 cells express greater amounts of IGFBP-2, our data implies that the diminished regulation of IGFBP-2 and loss of associated proteolytic fragments play a role in the increased metastatic behavior of these cells in vivo. Furthermore, our results suggest that either increased levels of intact IGFBP-2 or decreased levels of IGFBP-2 proteolytic fragments could serve as a biomarker to monitor for progression to AI-PCa.
authors.affiliation: Laboratory for Cancer Ontogeny and Therapeutics, Department of Biological Sciences, University of Delaware, Newark, Deleware 19716, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Degraff
authors.forename: Manisha
authors.initials: M
authors.lastname: Malik
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Kenichi
authors.initials: K
authors.lastname: Miyako
authors.forename: Lidia
authors.initials: L
authors.lastname: Rejto
authors.forename: Adam A
authors.initials: AA
authors.lastname: Aguiar
authors.forename: Diccon R E
authors.initials: DR
authors.lastname: Bancroft
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sikes
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000728:Androgens; D014408:Biomarkers, Tumor; D018971:Insulin-Like Growth Factor Binding Protein 2; D011944:Receptors, Androgen; D010450:Endopeptidases; C095329:IGFBP-2 protease