Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 9, Pages 1383-1401Publisher
WILEY-BLACKWELL
DOI: 10.1002/emmm.201202367
Keywords
androgen receptor; CCL2; epithelial-mesenchymal transition; prostate cancer; STAT3
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Funding
- NIH [CA127300, CA156700]
- DOD [W81XWH-10-1-0300]
- Taiwan Department of Health Clinical Trial and Research Center of Excellence Grant [DOH99-TD-B-111-004]
- China 973 National Program on Key Basic Research Project [2012CB518305]
- Grants-in-Aid for Scientific Research [25861413] Funding Source: KAKEN
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Increased CCL2 expression in prostate cancer (PCa) cells enhanced metastasis via macrophage recruitment. However, its linkage to androgen receptor (AR)-mediated PCa progression remains unclear. Here, we identified a previously unrecognized regulation: targeting AR with siRNA in PCa cells increased macrophage recruitment via CCL2 up-regulation, which might then result in enhancing PCa invasiveness. Molecular mechanism dissection revealed that targeting PCa AR with siRNA promoted PCa cell migration/invasion via CCL2-dependent STAT3 activation and epithelial-mesenchymal transition (EMT) pathways. Importantly, pharmacologic interruption of the CCL2/CCR2-STAT3 axis suppressed EMT and PCa cell migration, providing a new mechanism linking CCL2 and EMT. Simultaneously targeting PCa AR with siRNA and the CCL2/CCR2-STAT3 axis resulted in better suppression of PCa growth and metastasis in a xenograft PCa mouse model. Human PCa tissue microarray analysis suggests that increased CCL2 expression may be potentially associated with poor prognosis of PCa patients. Together, these results may provide a novel therapeutic approach to better battle PCa progression and metastasis at the castration resistant stage via the combination of targeting AR with siRNA and anti-CCL2/CCR2-STAT3 signalling.
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