RESUMEN
The adaptor protein CARD9 links detection of fungi by surface receptors to the activation of the NF-κB pathway. Mice deficient in CARD9 exhibit dysbiosis and are more susceptible to colitis. Here we examined the impact of Card9 deficiency in the development of colitis-associated colon cancer (CAC). Treatment of Card9-/- mice with AOM-DSS resulted in increased tumor loads as compared to WT mice and in the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissue. The impaired fungicidal functions of Card9-/- macrophages led to increased fungal loads and variation in the overall composition of the intestinal mycobiota, with a notable increase in C. tropicalis. Bone marrow cells incubated with C. tropicalis exhibited MDSC features and suppressive functions. Fluconazole treatment suppressed CAC in Card9-/- mice and was associated with decreased MDSC accumulation. The frequency of MDSCs in tumor tissues of colon cancer patients correlated positively with fungal burden, pointing to the relevance of this regulatory axis in human disease.
Asunto(s)
Proteínas Adaptadoras de Señalización CARD/metabolismo , Colitis/inmunología , Neoplasias del Colon/inmunología , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Células Supresoras de Origen Mieloide/fisiología , Animales , Proteínas Adaptadoras de Señalización CARD/genética , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Colitis/inducido químicamente , Colitis/genética , Neoplasias del Colon/genética , Disbiosis/genética , Humanos , Interferón gamma/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Supresoras de Origen Mieloide/microbiología , Regiones Promotoras Genéticas/genéticaRESUMEN
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 I:C) 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 I:C and the cell viability was measured. Results showed that poly I:C 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 I:C preferentially activated the TLR3-UNC93B1 signaling pathway to mediate this effect. Moreover, cotreatment of poly I:C 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 I:C and PTX synergistically inhibited the PTX-resistant tumor growth in vivo without side effects. In conclusion, our studies demonstrate that poly I:C 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 I:C for the chemotherapy sensitizing effect in a PTX-resistant tumor.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Interferón beta/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Paclitaxel/farmacología , Poli I-C/farmacología , Receptor Toll-Like 3/agonistas , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Interferón beta/genética , Proteínas de Transporte de Membrana/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Low frequency magnetic fields (LF-MFs) can affect cell proliferation in a cell-type and intensity-dependent way. Previous study has reported the anti-tumor effect of LF-MFs in lung cancers. Our previous study also optimized the intensity and duration of LF-MFs to effectively inhibit the proliferation of lung cancer cells. However, the anti-tumor mechanism of LF-MFs remains unclear, which limit the clinical application of LF-MFs in anti-tumor therapy. Here, in a well-established Lewis Lung Cancer (LLC) mouse model, we found that LF-MFs inhibit tumor growth and induce an autophagic cell death in lung cancer. We also found that LF-MFs could up-regulate the expression level of miR-486, which was involved in LF-MFs activated cell autophagy. Furthermore, we found B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a direct target of miR-486. miR-486 inhibit AKT/mTOR signaling through inhibiting expression of BCAP. Moreover, a decreased expression of miR-486 and an increased expression of BCAP were found in tumor tissues of lung cancer patients. Taken together, this study proved that LF-MFs can inhibit lung cancers through miR-486 induced autophagic cell death, which suggest a clinical application of LF-MFs in cancer treatment.