Suppression of androgen receptor signaling induces prostate cancer migration via activation of the <scp>CCL20</scp>–<scp>CCR6</scp> axis
Hiroshi Kano, Kouji Izumi, Kaoru Hiratsuka, Ren Toriumi, Ryunosuke Nakagawa, Shuhei Aoyama, Taiki Kamijima, Takafumi Shimada, Renato Naito, Suguru Kadomoto, Hiroaki Iwamoto, Hiroshi Yaegashi, Shohei Kawaguchi, Takahiro Nohara, Kazuyoshi Shigehara, Yoshifumi Kadono, Yohei Saito, Kyoko Nakagawa‐Goto, Kazuaki Yoshioka, Hiroki Nakata, Wen‐Jye Lin, Atsushi Mizokami
Abstract
The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.