Abstract
Androgen/androgen receptor (AR) signaling is a significant driver of prostate cancer progression, therefore androgen-deprivation therapy (ADT) is often used as a standard form of treatment for advanced and metastatic prostate cancer patients. However, after several years of ADT, prostate cancer progresses to castration-resistant prostate cancer (CRPC). Androgen/AR signaling is still considered an important factor for prostate cancer cell survival following CRPC progression, while recent studies have reported dichotomic roles for androgen/AR signaling. Androgen/AR signaling increases prostate cancer cell proliferation, while simultaneously inhibiting migration. As a result, ADT can induce prostate cancer metastasis. Several C-C motif ligand (CCL)-receptor (CCR) axes are involved in cancer cell migration related to blockade of androgen/AR signaling. The CCL2-CCR2 axis is negatively regulated by androgen/AR signaling, with the CCL22-CCR4 axis acting as a further downstream mediator, both of which promote prostate cancer cell migration. Furthermore, the CCL5-CCR5 axis inhibits androgen/AR signaling as an upstream mediator. CCL4 is involved in prostate carcinogenesis through macrophage AR signaling, while the CCL21-CCR7 axis in prostate cancer cells is activated by tumor necrotic factor, which is secreted when androgen/AR signaling is inhibited. Finally, the CCL2-CCR2 axis has recently been demonstrated to be a key contributor to cabazitaxel resistance in CRPC.
Highlights
Prostate cancer is among the most frequently diagnosed malignancies worldwide in men [1]
The CCL2-CCR2 axis is negatively regulated by androgen/androgen receptor (AR) signaling, with the CCL22-CCR4 axis acting as a further downstream mediator, both of which promote prostate cancer cell migration
CCL4 is involved in prostate carcinogenesis through macrophage AR signaling, while the CCL21-CCR7 axis in prostate cancer cells is activated by tumor necrotic factor, which is secreted when androgen/AR signaling is inhibited
Summary
Prostate cancer is among the most frequently diagnosed malignancies worldwide in men [1]. Genetic ablation of AR in prostate epithelial cells promotes the development of invasive prostate cancer [7], suggesting that therapeutic suppression of androgen/AR function induces unwanted signals that may promote the progression of surviving prostate cancer cells to an advanced metastatic stage. STAT3 activation was observed to increase CCL2 expression levels in C4-2 siAR cells These results suggest that androgen/AR signaling in prostate cancer cells may inhibit CCL2 and pSTAT3 expression through upregulation of PIAS3 [8,9]. Prostatic epithelial AR silencing via siAR promotes STAT3 activation and EMT in prostate cancer cells via CCL2 induction, which may be associated with a secretory phenotype and pro-invasive characteristics of prostate cancer cells [8,9]
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