Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling.
Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling.
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DOI：
10.1038/cddis.2013.270
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发表时间：
2013-08-08
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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尽管雄激素剥夺疗法（ADT）抑制前列腺癌（PCa）的生长，但其对PCa转移的总体影响仍不清楚。使用人（C4-2B/THP 1）和小鼠（TRAMP-C1/RAW264.7）PCa细胞-巨噬细胞共培养系统，我们发现目前使用的抗雄激素药物MDV 3100（恩杂鲁胺）或Casodex（比卡鲁胺）可促进巨噬细胞向PCa细胞迁移，从而导致PCa细胞侵袭增强。相反，AR降解增强剂ASC-J 9抑制巨噬细胞迁移和随后的PCa细胞侵袭。机制分析表明，Casodex/MDV 3100降低了AR介导的PIAS 3表达，并增强了pSTAT 3-CCL 2通路。CCR 2拮抗剂的加入逆转了Casodex/MDV 3100诱导的巨噬细胞迁移和PCa细胞侵袭。相反，ASC-J 9可以通过两条途径调节pSTAT 3-CCL 2信号传导：通过抑制PIAS 3表达的AR依赖性途径和通过直接抑制STAT 3磷酸化/活化的AR非依赖性途径。这些发现在原位注射TRAMP-C1细胞的体内小鼠模型中得到证实。总之，这些结果可能会引起对目前使用的ADT与促进PCa转移的抗雄激素的潜在担忧，并且可以提供一些新的和更好的治疗策略，其使用单独的ASC-J 9或同时靶向雄激素/AR信号传导和PIAS 3-pSTAT 3-CCL 2信号传导的组合疗法，以更好地对抗去势抵抗阶段的PCa生长和转移。
Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.
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影响因子：
7.3
作者：
Lee, Yu-Chen;Cheng, Chien-Jui;Huang, Miao;Bilen, Mehmet A.;Ye, Xiangcang;Navone, Nora M.;Chu, Khoi;Kao, Hsin-Hsin;Yu-Lee, Li-Yuan;Wang, Zhengxin;Lin, Sue-Hwa
通讯作者：
Lin, Sue-Hwa
影响因子：
168.9
作者：
Scher, Howard I.;Beer, Tomasz M.;Higano, Celestia S.;Anand, Aseem;Taplin, Mary-Ellen;Efstathiou, Eleni;Rathkopf, Dana;Shelkey, Julia;Yu, Evan Y.;Alumkal, Joshi;Hung, David;Hirmand, Mohammad;Seely, Lynn;Morris, Michael J.;Danila, Daniel C.;Humm, John;Larson, Steve;Fleisher, Martin;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
4.8
作者：
Chipuk, JE;Cornelius, SC;Danielpour, D
通讯作者：
Danielpour, D
影响因子：
11.2
作者：
Kleeberger, Wolfram;Bova, G. Steven;Berman, David M.
通讯作者：
Berman, David M.
影响因子：
--
作者：
KYPRIANOU, N;ISAACS, JT
通讯作者：
ISAACS, JT