TLR9 signaling through NF-κB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells
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Dayson Moreira1, Qifang Zhang1, Dewan Md S. Hossain1, Sergey Nechaev1,8, Haiqing Li2, Claudia M. Kowolik3, Massimo D’Apuzzo4, Stephen Forman5, Jeremy Jones6, Sumanta K. Pal7, Marcin Kortylewski1
1Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
2Bioinformatics Core Facility, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
3Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
4Department of Pathology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
5Department of Hematologic Malignancies, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
6Department of Cell Biology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
7Department of Medical Oncology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
8Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
Marcin Kortylewski, e-mail: [email protected]
Keywords: TLR9, prostate cancer, RELA, STAT3, tumor-propagating cells
Received: April 29, 2015 Accepted: May 09, 2015 Published: May 22, 2015
Prostate cancer progression was associated with tumorigenic signaling activated by proinflammatory mediators. However, the etiology of these events remains elusive. Here, we demonstrate that triggering of the innate immune receptor, Toll-like Receptor 9 (TLR9), in androgen-independent prostate cancer cells initiates signaling cascade leading to increased tumor growth and progression. Using limited dilution/serial transplantation experiments, we show that TLR9 is essential for prostate cancer cells’ potential to propagate and self-renew in vivo. Furthermore, low expression or silencing of TLR9 limits the clonogenic potential and mesenchymal stem cell-like properties of LNCaP- and PC3-derived prostate cancer cell variants. Genome-wide transcriptional analysis of prostate cancer cells isolated from xenotransplanted TLR9-positive and -negative tumors revealed a unique gene expression signature, with prominent upregulation of inflammation- and stem cell-related markers. TLR9 signaling orchestrated expression of critical stem cell-related genes such as NKX3.1, KLF-4, BMI-1 and COL1A1, at both mRNA and protein levels. Our further analysis identified that TLR9-induced NF-κB/RELA and STAT3 transcription factors co-regulated NKX3.1 and KLF4 gene expression by directly binding to both promoters. Finally, we demonstrated the feasibility of using TLR9-targeted siRNA delivery to block RELA- and STAT3-dependent prostate cancer cell self-renewal in vivo. The intratumoral administration of CpG-RELAsiRNA or CpG-STAT3siRNA but not control conjugates inhibited growth of established prostate tumors and reduced clonogenic potential of cancer cells. Overcoming cancer cell self-renewal and tumor-propagating potential by targeted inhibition of TLR9 signaling can provide therapeutic strategy for late-stage prostate cancer patients.
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