*5.2. CCL22-CCR4 Axis*

Tissue microarray analysis revealed a correlation between staining intensity of CCR4 and prostate cancer progression, however no such correlation existed with CCR2, despite the fact that CCR2 and CCR4 intensities were correlated with one another. Therefore, the CCL22-CCR4 axis may prove a more significant driver of prostate cancer migration and invasion than the CCL2-CCR2 axis [11]. Phosphorylation of Akt proteins is more effectively inhibited by CCR4 antagonists than CCR2 antagonists, further indicating the efficiency of CCR4 antagonist therapy against prostate cancer migration and invasion [11]. Akt activation is controlled by phosphorylation of the two key residues threonine 308 (Thr308) and serine 473 (Ser473) [42], and their phosphorylation promotes prostate cancer cell growth, proliferation, motility, and survival [43–45]. Our previous results indicated that the CCL22-CCR4 axis controls phosphorylation of Ser473. It has been previously been demonstrated that CCL2 promotes prostate cancer cell proliferation, migration, and survival via Akt-activation-dependent mechanisms [46–48]. Taken together, these results indicate that the CCL22-CCR4 axis may prove to be a better therapeutic target than the CCL2–CCR2 axis for prostate cancer patients. CCR4 expression is observed on tumor cells derived from the majority of adult T-cell leukemia-lymphoma (ATL) patients, therefore mogamulizumab, an anti-CCR4 antibody, has been approved in Japan for the treatment of relapsed/refractory ATL [49,50]. In addition, potent inhibition of Akt signaling using an Akt inhibitor was associated with a tolerable safety profile and meaningful disease control in a subgroup of patients with solid tumors during phase 1 and 2 trials [51,52]. Application of such CCL22-CCR4 targeting agents for therapy of CRPC patients is expected in the near future.

### *5.3. CCL5-CCR5 Axis and Others*

In a recent study of ours that focused on the effects of coffee compounds on prostate cancer cells, the coffee diterpenes kahweol acetate and cafestol were observed to synergistically inhibit prostate cancer cell proliferation and migration [53]. These diterpenes were capable of inhibiting androgen/AR signaling without inducing prostate cancer cell secretion on CCL2 and CCL5 [53]. It is noteworthy that expression of CCR2 and CCR5, receptors for CCL2 and CCL5, respectively, visibly decreased following diterpene administration in prostate cancer cells [53]. Kahweol acetate and cafestol may, therefore, represent potential therapeutic candidates, especially in combination therapy for the treatment of both castration-sensitive prostate cancer and CRPC [53].

### **6. CCL Involvement Various Pathways of Prostate Cancer Progression**
