Modulating TLR9 Activation for Lung Cancer Therapy
Abstracts
Initial Award Abstract |
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Lung cancer is the commonest cause of cancer-related death throughout the world. Cigarette smoking is highly correlated with the incidence of lung cancer accounting for around 90% of the causes in men and 80% of the causes in women. Synthetic CpG containing oligo-deoxynucleotides (CpG-ODN) are a relative new class of agents for treatment of lung cancer. In combination with conventional standard platinum or taxane chemotherapy, CpG-ODN have been used in phase III clinical trail for non-small-cell lung cancer treatment. These CpG-ODN have a favorable safty profile. Currently, the major direction to further develope them for more effective cancer therapy is to improve their efficacy for monotherapy or combinational therapy. Toll-like receptor 9 (TLR9) is a member of TLR family comprised by 10 members, TLR1-10, in human cells. These TLRs have an essential role in recognition of bacterial pathogens to trigger host defense in response to microbial invasions. TLR9 is preferentially expressed in immune cells especially in B cells, plasmacytoid dendritic cells and expressed at lower levels in respiratory cells and lung cancer cells. This receptor recognizes non-methylated bacterial DNA as well as CpG-ODN. The antitumor effect of CpG-ODN is meditated by TLR9. Upon stimulation, TLR9 triggers Th1 immune responses including increased synthesis of cytokines such as IL-12 and interferon-fx (IFN-fx), leading to maturation, differentiation, and proliferation of natural killer (NK) cells, T cells and monocytes. These immunoadjuvant effects facilitate eradiaction of malignant cells. Recently, we identified a novel TLR9 interacting protein termed Triad3A which is a member of a group of related proteins resulting from alternative splicing of the Triad3 gene. The Triad3A is an E3 ubiquitin-protein ligase that promotes ubiquitination and proteolytic degradation of TLR9 and several signaling molecules downstream to TLRs. Overexpression of Triad3A blocks CpG-ODN induced NF-kB activation in cells. Conversely, reduction in endogenous Triad3A by siRNA enhances cellular responses to CpG-ODN. These results suggest that Triad3A is a component of an endogenous control mechanism for TLR9 activation. In addation, we have generated a gene-trapped Triad3A knockout mice model. Preliminary results using Triad3A knockout splenocytes and bone marrow derived macrophages indicated that the production of IL-12 and IFN-fx in these cells were increased in response to CpG-ODN stimulation. We hypothesize that the the extent of TLR9 activation upon stimulation could be important in determining the efficacy of CpG-ODN in lung cancer therapy. To test this hypothesis, in this project we will: (1) utilize the Triad3A knockout mice to establish lung cancer animal models, and investigate whether reduction of Triad3A activity enhances the efficacy of CpG-ODN in inhibition of lung cancer growth, and (2) investigate the extent and the molecular basis of CpG-ODN induced immunological responses in the Triad3A knockout mice. Completion of this project will help us to elucidate whether Triad3A is a molecular target to enhance the therapeutic effect of CpG-ODN for lung cancer treatment, and provide us information for additional therapeutic strategies with CpG-ODN. |
Publications
| NF-kappaB activation primes cells to a pro-inflammatory polarized response to a TLR7 activation. |
| Periodical: Biochemical Journal |
Index Medicus: |
| Authors: Lee J, Hayashi M, Lo JF, Fearns C, Chu WM, Luo Y, Xiang R, Chuang TH |
ART |
| Yr: 2009 |
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| NF-kappaB activation primes cells to a pro-inflammatory polarized response to a TLR7 activation. |
| Periodical: Biochemical Journal |
Index Medicus: |
| Authors: Lee J, Hayashi M, Lo JF, Fearns C, Chu WM, Luo Y, Xiang R, Chuang TH |
ART |
| Yr: 2009 |
Vol: |
Nbr: |
Abs: |
Pg: |
