Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility

Autor: Hiroaki Misonou, Jordy J. Hsiao, Jinhee Lee, Jiahui Wang, James S. Trimmer, Brandon H. Ng, Melinda M. Smits, Harryl D. Martinez, Jhullian J Alston, Rohini J. Jasavala, Michael E. Wright
Rok vydání: 2015
Předmět:
CCR1
Male
Cancer Research
Chemokine receptor CCR5
Cell motility
CCR8
Androgen
Chemokine receptor
Cell Movement
Receptors
Medicine
2.1 Biological and endogenous factors
Aetiology
CXCR
Cancer
Prostate cancer
Tumor
biology
Prostate Cancer
Cell biology
Gene Expression Regulation
Neoplastic
Androgen receptor
Oncology
Receptors
Androgen
Androgens
Public Health and Health Services
RNA Interference
Research Article
Signal Transduction
Biotechnology
Urologic Diseases
Receptors
CXCR4
medicine.medical_specialty
Oncology and Carcinogenesis
Motility
Cell Line
Cell Line
Tumor
Internal medicine
LNCaP
Genetics
CXCL10
Humans
Oncology & Carcinogenesis
CXCL14
Cell Proliferation
Receptors
CXCR
CXCR4
Neoplastic
business.industry
Prostatic Neoplasms
CXCR7
Chemokine CXCL12
Chemokine CXCL11
Endocrinology
Gene Expression Regulation
biology.protein
business
Zdroj: BMC cancer, vol 15, iss 1
Hsiao, JJ; Ng, BH; Smits, MM; Wang, J; Jasavala, RJ; Martinez, HD; et al.(2015). Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility. BMC Cancer, 15(1). doi: 10.1186/s12885-015-1201-5. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/4pj092hv
BMC Cancer
DOI: 10.1186/s12885-015-1201-5.
Popis: Background Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear. Methods Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12. Results Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein. Conclusions Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1201-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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