Abstract
BackgroundCannabinoids bind to cannabinoid receptors CB1 and CB2 and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB2 may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.Methodology/Principal FindingsWe observed high expression of both CB2 and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB2-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4), highly metastatic clone of MDA-MB-231 (SCP2) and NT 2.5 cells (derived from MMTV-neu) by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems.Conclusions/SignificanceThis study provides novel insights into the crosstalk between CB2 and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB2 receptors could be used for developing innovative therapeutic strategies against breast cancer.
Highlights
Cannabinoids exert their effects by binding with two heptahelical Gai/Gao-protein-coupled receptors, CB1 and CB2
Synthetic cannabinoids that bind to cannabinoid receptors CB1 and CB2 have been shown to inhibit migration, metastasis, and invasion of various cell types including breast cancer cells [4,5,6,37,41]
The majority of breast cancers have been shown to overexpress chemokine receptor CXCR4, which has been correlated with poor prognosis [34]
Summary
Cannabinoids exert their effects by binding with two heptahelical Gai/Gao-protein-coupled receptors, CB1 and CB2. Cannabinoid receptors have been shown to modulate several signaling pathways involved in the control of cell survival, not much is known about their role in the regulation of chemokine receptor CXCR4mediated signaling in tumors [5,6,14]. We report that a synthetic non-psychoactive cannabinoid that binds to cannabinoid receptor CB2 may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis
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