title: Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation.
abstract: 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.
authors: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA.
authors: Kouji
authors: K
authors: Izumi
authors: Lei-Ya
authors: LY
authors: Fang
authors: Atsushi
authors: A
authors: Mizokami
authors: Mikio
authors: M
authors: Namiki
authors: Lei
authors: L
authors: Li
authors: Wen-Jye
authors: WJ
authors: Lin
authors: Chawnshang
authors: C
authors: Chang
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D046228:Microarray Analysis; D009362:Neoplasm Metastasis / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: C410798:AR protein, human; C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D054390:Receptors, CCR2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: CCL2; STAT3; androgen receptor; epithelial-mesenchymal transition; prostate cancer
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