Research Papers:

Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells

Wai Hoe Lau, Xiphias Ge Zhu, Shamaine Wei Ting Ho, Shu Chun Chang and Jeak Ling Ding _

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Oncotarget. 2017; 8:32884-32904. https://doi.org/10.18632/oncotarget.15862

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Wai Hoe Lau1, Xiphias Ge Zhu1, Shamaine Wei Ting Ho1, Shu Chun Chang1,2 and Jeak Ling Ding1

1Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore

2Taipei Medical University, College for Medical Science and Technology, Taipei 110, Taiwan

Correspondence to:

Jeak Ling Ding, email: [email protected]

Keywords: lung cancer cells, polyI:C-TLR3 suppression of survival and metastasis, anti-IL6 antibody, JAK2/STAT3 antagonists, cytokines and caspase 3/7 apoptosis

Received: November 30, 2016    Accepted: February 07, 2017    Published: March 02, 2017


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.

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