Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells.
Oncotarget
; 8(20): 32884-32904, 2017 May 16.
Article
in En
| MEDLINE
| ID: mdl-28427199
ABSTRACT
Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyIC, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyIC reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyIC 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 polyIC, expressed low-to-medium level of TLR3 protein, and were susceptible to polyIC treatment. By contrast, NCI-H1299, which endogenously expresses high level of TLR3 protein, was insensitive to polyIC. We showed that polyIC 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 polyIC. Thus, NCI-H358 was resistant to the inhibition of cytokine-dependent metastasis. NCI-H1299, which was unresponsive to polyIC, did not produce any of the pro-inflammatory cytokines. Treatment of A549 with a combination of polyIC and anti-IL6 antibody significantly decreased IL6 production, and enhanced polyIC-mediated killing and suppression of oncogenicity and metastasis. While polyIC stimulated the phosphorylation of STAT3 and JAK2, blockade of these proteins enhanced polyIC-mediated suppression of survival and metastasis. Taken together, polyIC alone provoked apoptosis of lung cancer cells that express low-to-medium levels of functional TLR3 protein. The combinatorial treatment with polyIC and anti-IL6 enhanced polyIC-mediated anticancer activities through IL6/JAK2/STAT3 signalling, and apoptosis via TLR3-mediated caspase 3/8 pathway.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antineoplastic Combined Chemotherapy Protocols
/
Interleukin-6
/
Poly I-C
/
Antineoplastic Agents, Immunological
/
Lung Neoplasms
Limits:
Humans
Language:
En
Journal:
Oncotarget
Year:
2017
Type:
Article
Affiliation country:
Singapore