CXCR4 Is a Novel Target of Cancer Chemopreventative Isothiocyanates in Prostate Cancer Cells

Abstract

Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the isothiocyanates affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNA interference of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma.

Proinflammatory CXCL12–CXCR4/CXCR7 Signaling Axis Drives Myc-Induced Prostate Cancer in Obese Mice

“…Here, by using both in vivo and in vitro models, we show that the SVF of ppWAT is a rich source of growth factors, cytokines and chemokines that are produced at high levels in obese mice. The role of CXCL12-CXCR4 axis in progression of various cancers including PCa is well documented [28–31]. However, the cell source of CXCL12 has remained unclear and whether this chemokine gradient contributes to caner-promoting effects of obesity has remained a subject of debate.…”

“…CXCR4 has been shown to be a key receptor in mediating the metastasis of multiple types of tumors [27]. The role of CXCL12-CXCR4 axis in cancer cell migration, invasion and metastasis has been demonstrated [28–31]. AMD3100, a CXCR4 inhibitor, sensitizes PCa to chemotherapy [32], however the main source of CXCL12 and its contribution to obesity-associated cancer progression has not been investigated.…”

Nonhuman primate model of persistent erectile and urinary dysfunction following radical prostatectomy: Feasibility of minimally invasive therapy

“…Preliminary and experimental studies demonstrated evidences that CXCL12/CXCR4 signaling pathway may be involved in metastatic prostate cancer progression . Prostate cancer cells isolated from bone metastasis had overexpression of CXCR4 and CXCR7 chemokine receptors .…”

“…Preliminary and experimental studies demonstrated evidences that CXCL12/CXCR4 signaling pathway may be involved in metastatic prostate cancer progression . Prostate cancer cells isolated from bone metastasis had overexpression of CXCR4 and CXCR7 chemokine receptors . Analysis of CXCR4 expression in humans using high‐density microarrays from a cohort of 600 patients demonstrated elevated levels of this chemokine receptor in metastatic prostate cancer .…”

Broccoli Sprouts Delay Prostate Cancer Formation and Decrease Prostate Cancer Severity with a Concurrent Decrease in HDAC3 Protein Expression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice

“…SFN has been shown to inhibit the initiation of cancer by blocking damage caused by carcinogens through the induction of phase 2 enzymes via kelch-like ECH associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling ( 10–13 ). In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer, broccoli consumption and/or SFN treatment has been shown to slow prostate cancer growth and metastasis ( 8 , 9 , 14 , 15 ). Several potential mechanisms have been implicated, including the induction of Nrf2-related pathways, inhibition of the cancer-promoting Akt signaling cascade, suppression of a chemokine receptor (CXCR4), and through augmenting the lytic activity of natural killer cells ( 8 , 9 , 14 , 15 ).…”