Abstract
Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyI:C, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyI:C reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyI:C suppressed the proliferation and survival of metastatic (NCI-H358 and NCI-H292) and non-metastatic (A549) lung cancer cells. Notably, A549, NCI-H292 and NCI-H358 which are inducible by polyI:C, expressed low-to-medium level of TLR3 protein, and were susceptible to polyI:C treatment. By contrast, NCI-H1299, which endogenously expresses high level of TLR3 protein, was insensitive to polyI:C. We showed that polyI:C stimulated pro-inflammatory cytokines associated with survival and metastasis in a cell type-specific manner. While A549 and NCI-H292 released high levels of IL6, IL8 and GRO, the NCI-H358 cells endogenously secretes abundant levels of these cytokines, and was not further induced by polyI:C. Thus, NCI-H358 was resistant to the inhibition of cytokine-dependent metastasis. NCI-H1299, which was unresponsive to polyI:C, did not produce any of the pro-inflammatory cytokines. Treatment of A549 with a combination of polyI:C and anti-IL6 antibody significantly decreased IL6 production, and enhanced polyI:C-mediated killing and suppression of oncogenicity and metastasis. While polyI:C stimulated the phosphorylation of STAT3 and JAK2, blockade of these proteins enhanced polyI:C-mediated suppression of survival and metastasis. Taken together, polyI:C alone provoked apoptosis of lung cancer cells that express low-to-medium levels of functional TLR3 protein. The combinatorial treatment with polyI:C and anti-IL6 enhanced polyI:C-mediated anticancer activities through IL6/JAK2/STAT3 signalling, and apoptosis via TLR3-mediated caspase 3/8 pathway.
Highlights
Non-small cell lung cancer (NSCLC) is the most common type of lung carcinoma with poor prognosis [1]
We found variations of toll-like receptor 3 (TLR3) mRNA expression amongst the cancer types tested (Supplementary Figure 1A), and heterogeneity was observed within the different cell lines of the lung and hepatocellular cancers (HCC)
Lung cancer cell lines, A549 and NCI-H292, express substantial endogenous levels of TLR3 mRNA when not treated with polycytidilic acid (polyI):C (Figure 1A, NT white bars) but they express low levels of TLR3 protein (Figure 1B and Supplementary Figure 1B) compared to those of NCI-H358 and NCI-H1299
Summary
Non-small cell lung cancer (NSCLC) is the most common type of lung carcinoma with poor prognosis [1]. Tumor cells aberrantly express an array of TLRs [11], whereupon activation, may perform dual opposing functions, either to enhance host anti-tumor immunity or promote cancer survival [12, 13]. TLR3, which is aberrantly expressed in hepatocellular carcinoma (HCC) [14], breast [15], melanoma [16], and metastatic lung carcinoma [17], was recently reported to trigger apoptosis in these cancers, when induced. In mice models of breast and lung cancers, TLR3 activation was reported to: (a) elicit chemoattraction of cytotoxic lymphocytes to the growing tumor [15, 19, 20], (b) induce secretion of type I interferon (IFN) and inflammatory cytokine/chemokine and (c) enhance anti-tumor immune responsiveness [16, 21]
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