Abstract
For head and neck squamous cell carcinoma (HNSCC), the local invasion and distant metastasis represent the predominant causes of mortality. Targeted inhibition of chemokines and their receptors is an ongoing antitumor strategy established on the crucial roles of chemokines in cancer invasion and metastasis. Herein, we showed that C-C motif chemokine ligand 2 (CCL2)- C-C motif chemokine receptor 4 (CCR4) signaling, but not the CCL2- C-C motif chemokine receptor 2 (CCR2) axis, induces the formation of the vav guanine nucleotide exchange factor 2 (Vav2)- Rac family small GTPase 1 (Rac1) complex to activate the phosphorylation of myosin light chain (MLC), which is involved in the regulation of cell motility and cancer metastasis. We identified that targeting CCR4 could effectively interrupt the activation of HNSCC invasion and metastasis induced by CCL2 without the promoting cancer relapse observed during the subsequent withdrawal period. All current findings suggested that CCL2-CCR4-Vav2-Rac1-p-MLC signaling plays an essential role in cell migration and cancer metastasis of HNSCC, and CCR4 may serve as a new potential molecular target for HNSCC therapy.
Highlights
Cell migration is a crucial process for the invasive and metastasis of cancer [1, 2]
C motif chemokine ligand 2 (CCL2) enhances head and neck squamous cell carcinoma (HNSCC) cell motility via promoting Rac1phosphorylated MLC (p-MLC) activation Given that the Rac family small GTPase 1 (Rac1)-p-MLC signal had been reported to play an important role in cell motility by promoting the contractile motion of the myosin light chain, we used interruption approaches with a specific inhibitor to block Rac1 (100 μM, NSC 23766, MedChemExpress, Monmouth Junction, NJ), we found that the cell migration was suppressed in HNSCC cells treated with CCL2 (Fig. 3A, B)
We demonstrated that the CCL2-chemokine receptor 4 (CCR4) axis, not CCL2-chemokine receptor 2 (CCR2) signaling, mediates the CCL2induced migration and invasion of human HNSCC cells and targeted inhibition of CCR4 significantly inhibit the invasion and metastasis of HNSCC xenografts in the nude mouse without causing relapse during the cessation of CCL2 antibody therapy
Summary
Cell migration is a crucial process for the invasive and metastasis of cancer [1, 2]. An increasing number of evidence has revealed that targeted drugs that disrupt cell migration led to the significant improvement in five-year survival rates of prostate and breast cancer patients with metastasis [3]. Chemokines and their receptors are essential coordinators of directed migration of cancer cells and cell–cell interactions and significantly impact tumor development. A recent study indicated that directly targeting CCL2 may provoke unexpected adverse effects, indicating that cessation of CCL2 inhibition leads to a rebound in the number of circulating monocytes, increasing angiogenesis, promoting metastases, and accelerating death in the breast cancer model [15]. Avoiding the adverse effects during the direct intervention of CCL2 represents an essential challenge of current CCL2-CCR2 axistargeted antitumor therapy
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