title: Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK.
abstract: Interleukin-8 (IL-8), a chemokine implicated in the metastasis and angiogenesis of a variety of cancers, has been reported to be overexpressed in prostate cancer. In this study, we ascribe a new role for IL-8 in prostate cancer progression using LNCaP cells. We demonstrate that IL-8 activates the androgen receptor and confers androgen-independent growth, while serving as a potent chemotactic factor. Our evaluation of the possible signal pathways involved in androgen-independence and cell migration shows that the tyrosine kinases Src and FAK (focal adhesion kinase) are involved in IL-8-induced signaling. Pharmacological and genetic inhibitors of Src and FAK interfere with IL-8-induced cell migration, while only the Src inhibitor was able to repress androgen-independent growth. This suggests that both growth and migration depend on the activity of Src, whereas cell migration also requires the activation of FAK. Our evidence that IL-8-induced androgen-independent growth is, at least in part, due to androgen receptor activation includes (1) an inhibitor of androgen receptor activity diminishes cell growth; (2) androgen receptor transactivation potential is augmented by IL-8 and (3) androgen receptor is recruited to the promoter of prostate specific antigen (PSA) upon IL-8 treatment, based on chromatin immunoprecipitation experiments. Taken together, our data suggest that in addition to its role in metastasis and angiogenesis, IL-8 may also serve as a facilitator for androgen-independent transition of prostate cancers. To our knowledge, this is the first report about the tyrosine kinase signals and androgen receptor activation induced by IL-8 in prostate cancer cells. The observation that IL-8 mediates its growth and chemotactic effects via Src and FAK suggests the potential use for tyrosine kinase inhibitors at early stage of prostate cancer development.
authors.affiliation: Department of Microbiology and Immunology, Stanford University, School of medicine, Stanford, CA 94305, USA.
authors.forename: Li-Fen
authors.initials: LF
authors.lastname: Lee
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Louie
authors.forename: Sonal J
authors.initials: SJ
authors.lastname: Desai
authors.forename: Joy
authors.initials: J
authors.lastname: Yang
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Chen
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Evans
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000728:Androgens / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002633:Chemotaxis / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D011233:Precipitin Tests; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000728:Androgens; D002843:Chromatin; D016209:Interleukin-8; D011944:Receptors, Androgen; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D019061:src-Family Kinases; D017430:Prostate-Specific Antigen