Abstract
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.
Highlights
In developed countries, prostate cancer is the second leading cause of male cancer-related deaths with lack of effective therapies for late-stage cancer patients [1]
Previous studies reported that prostate cancer cells express innate immune receptors, such as Toll-like Receptor 9 (TLR9), normally restricted to the hematopoietic cell lineage [2, 5, 7]
We demonstrate for the first time that TLR9 expression promotes tumor-propagating potential of prostate cancer cells in vivo
Summary
Prostate cancer is the second leading cause of male cancer-related deaths with lack of effective therapies for late-stage cancer patients [1]. Tissue stress and injury involve activation of Toll-like receptors (TLRs) in various hematopoietic cells [4]. Cancer cells can upregulate TLR9 in response to genotoxic stress caused by irradiation or chemotherapy [6]. Recent studies documented that mitochondrial DNA (mtDNA) released as a result of sterile tissue injury activates TLR9 causing pathologic inflammatory responses [9, 10]. Downstream TLR9 signaling involves NF-κB transcription factor, which regulate expression of proinflammatory and survival mediators [4]. TLR9 signaling is tightly controlled at multiple levels by the signal transducer and activator of transcription 3 (STAT3) [11, 12]. Little is known about downstream effects of TLR9 signaling in human cancer cells. There is compelling evidence on the role of NF-κB and STAT3 in prostate cancer cell proliferation, survival and androgen-independence. [15,16,17,18]
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