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

Abstract

BackgroundIdentifying 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.MethodsImmunocytochemistry, 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.ResultsHere 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.ConclusionsOverall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1201-5) contains supplementary material, which is available to authorized users.

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

“…However, the interaction of androgen with the CXCL12/CXCR4/CXCR7 system in the breast had not been studied until now. Androgen has been implicated in the regulation of breast cancer cell proliferation [55] and data from prostate cancer show that androgen modulates CXCR4 and stimulate cellular migration [23, 26], a result we extend to breast cancer in this investigation. In addition, castrated male rats have lower CXCL12 levels compared to control rats and after induced myocardial infarction, they display reduced ability to recruit CD34+ bone marrow cells to ischemic areas of the myocardium [25].…”

“…The relation of estrogen and ERs with CXCL12 and CXCR4 in breast cancer cell proliferation and metastatic potential has been examined in depth during the last decade [17-22]. However, only a few reports have investigated the possible interaction between androgen/AR and CXCL12 and its receptors, mostly describing pro-migratory effects in prostate cancer [23-26]. …”

Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1

“…Taken together, our PLA results suggest that first, under control conditions (no E 2 , no LPS), GPR30 and ERa36 display a small amount of physical interaction, and none of these molecules interacts with p65. Furthermore, the investigators reported an "unexpected" CXCR7 localization in the nuclear compartment that modulates AR-mediated transcription [39]. Third, in the presence of LPS, both ERa36 and GPR30/ GPER1 strongly interact with NF-kB.…”

“…1B, lower). Nuclear localization of a G-coupled receptor has also recently been reported for CXCR7, interacting with another nuclear receptor superfamily member (AR) [39]. 1B.…”

MiR‐206 inhibits proliferation and migration of prostate cancer cells by targeting CXCL11

“…Welsh et al detected that CXCL11 was highly expressed in PCa samples . CXCL11 regulated androgen‐regulated genes (ARGs) in LNCAP prostate‐tumor cells . In addition, CXCL11 could result in vascular smooth muscle cells proliferation and inhibited endometrial cancer growth with different CXCR3 isoforms .…”