title: Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation.
abstract: The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Seaton
authors.forename: Paula
authors.initials: P
authors.lastname: Scullin
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Maxwell
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.forename: Johanna
authors.initials: J
authors.lastname: Pettigrew
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gallagher
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.forename: David J J
authors.initials: DJ
authors.lastname: Waugh
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014105:Tosyl Compounds / Q000494:pharmacology; D014162:Transfection
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D016209:Interleukin-8; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D023063:Receptors, Interleukin-8B; D014105:Tosyl Compounds; C053541:bicalutamide