Toll-like receptor 3 agonist poly I:C reinforces the potency of cytotoxic chemotherapy via the TLR3-UNC93B1-IFN-ß signaling axis in paclitaxel-resistant colon cancer.
J Cell Physiol
; 234(5): 7051-7061, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30387134
ABSTRACT
Type I interferon (IFN) signaling in neoplastic cells has a chemo-sensitizing effect in cancer therapy. Toll-like receptor 3 (TLR3) activation promotes IFN-ß production, which induces apoptosis and impairs proliferation in some cancer cells. Herein, we tested whether the TLR3 agonist polyinosinic polycytidylic acid (poly IC) can improve chemotherapeutic efficacy in paclitaxel (PTX) resistant cell lines. Human colon cancer cell lines HCT116, SW620, HCT-8 (sensitive to PTX), and HCT-8/PTX (resistant to PTX) were treated with poly IC and the cell viability was measured. Results showed that poly IC specifically impaired the cell viability of HCT-8/PTX by simultaneously promoting cell apoptosis and inhibiting cell proliferation. In addition, when TLR3 was overexpressed in HCT-8/PTX cells, we found that TLR3 contributed to the production of IFN-ß that reduced cell viability, and poly IC preferentially activated the TLR3-UNC93B1 signaling pathway to mediate this effect. Moreover, cotreatment of poly IC and PTX acted synergistically to induce cell apoptosis of HCT-8/PTX via upregulating the expression of TLR3 and its molecular chaperone UNC93B1, assisting in the secretion of IFN-ß. Notably, a combination of poly IC and PTX synergistically inhibited the PTX-resistant tumor growth in vivo without side effects. In conclusion, our studies demonstrate that poly IC reinforces the potency of cytotoxic chemotherapeutics in PTX-resistant cell line through the TLR3-UNC93B1-IFN-ß signaling pathway, which supplies a novel mechanism of poly IC for the chemotherapy sensitizing effect in a PTX-resistant tumor.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Membrana Transportadoras
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Neoplasias Colorretais
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Poli I-C
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Interferon beta
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Paclitaxel
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Resistencia a Medicamentos Antineoplásicos
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Receptor 3 Toll-Like
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Antineoplásicos Fitogênicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article