title: Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro.
abstract: Advanced prostate cancers preferentially metastasize to bone, suggesting that this tissue produces factors that provide a suitable microenvironment for prostate cancer cells. Recently, it has become clear that even in antiandrogen-resistant cancers, the androgen receptor (AR)-signaling axis is required for prostate cancer progression. Therefore, we hypothesized that AR may be involved in the regulation of pathways that are responsible for the homing of prostate cancer cells to select microenvironments. In support of this hypothesis, we have determined that chemokine (C-X-C motif) receptor 4 (CXCR4), the receptor for the chemokine CXCL12, is up-regulated in prostate cancer cells in response to androgens. Given that the levels of CXCL12 are elevated at sites of known prostate cancer metastases such as bone, these results suggest that androgens may influence prostate cancer metastasis. Specifically, we demonstrate that androgens increase the levels of both CXCR4 mRNA and functional protein in LNCaP prostate cancer cells. Importantly, androgens enhanced the migration of LNCaP cells toward a CXCL12 gradient, an effect that could be blocked by the specific CXCR4 antagonist AMD3100. Interestingly, CXCR4 is not directly regulated by androgens but rather is positively up-regulated by Krüppel-like factor 5 (KLF5), a transcription factor that we have shown to be an early, direct target of AR. Further, KLF5 is both required and sufficient for androgen-mediated CXCR4 expression and migration toward CXCL12. Taken together, these findings demonstrate that AR can utilize the CXCL12/CXCR4 axis through induction of KLF5 expression to promote prostate cancer progression and highlight the potential utility of CXCR4 antagonists as prostate cancer therapeutics.
authors.affiliation: Duke University Medical Center, Department of Pharmacology, Box 3813, Durham, North Carolina 27710, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Sherk
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Wittmann
authors.forename: John D
authors.initials: JD
authors.lastname: Norris
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.forename: James D
authors.initials: JD
authors.lastname: Joseph
authors.forename: Aidan P
authors.initials: AP
authors.lastname: Toner
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*
chemical_list: D000728:Androgens; D054377:Chemokine CXCL12; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D019718:Receptors, CXCR4