RESUMEN
Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRß is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRß, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRß, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.
Asunto(s)
Apoptosis , Receptores Nucleares Huérfanos/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacología , Proteínas Portadoras/metabolismo , Caspasa 1/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Conexinas/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Hidrocarburos Fluorados/farmacología , Receptores X del Hígado , Ratones Endogámicos BALB C , Proteína con Dominio Pirina 3 de la Familia NLR , Trasplante de Neoplasias , Proteínas del Tejido Nervioso/metabolismo , Receptores Nucleares Huérfanos/agonistas , Sulfonamidas/farmacología , Carga Tumoral/efectos de los fármacosRESUMEN
Accumulating evidence suggests that the success of some anticancer therapies not only relies on their direct cytotoxicity on tumor cells but also on their ability to promote anticancer immune responses. However, immunosuppressive cells such as Myeloid Derived Suppressor Cells (MDSC) that are generated during tumor progression blunt antitumor immune responses and thus represent a major obstacle to the clinical implementation of immunotherapy protocols. We have recently identified 5-Fluorouracil (5-FU) as an anticancer agent that selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5-FU increased IFNγ secretion by tumor specific CD8(+) T cells infiltrating the tumor and promoted T-cell dependent antitumor responses in vivo, suggesting that some anticancer therapies can reverse tumor-mediated immunosuppression. Here, we review the molecular pathways leading to the induction of MDSC in cancer and discuss how different anticancer agents successfully target these cells in vivo, thereby restoring potent anticancer immunity.
Asunto(s)
Antineoplásicos/uso terapéutico , Tolerancia Inmunológica/efectos de los fármacos , Terapia de Inmunosupresión , Células Mieloides/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Animales , Apoptosis/inmunología , Fluorouracilo/uso terapéutico , Humanos , Interferón gamma/metabolismo , Ratones , Células Mieloides/inmunología , Linfocitos T/inmunologíaRESUMEN
Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas.
Asunto(s)
Neoplasias de la Mama/genética , Factor de Transcripción GATA1/fisiología , Proteínas Asociadas a Microtúbulos/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Sitios de Unión , Neoplasias de la Mama/química , Línea Celular Tumoral , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis , Fosforilación , Survivin , Regulación hacia ArribaRESUMEN
BACKGROUND: Resistance to trastuzumab is often observed in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been shown to involve multiple potential mechanisms. We examined the ability of microarray analyses to determine the potential markers of pathological complete response (pCR). METHODS: We conducted an analysis of tumours from 38 patients with locally advanced HER2-positive breast cancer who had received trastuzumab combined with docetaxel. Quantitative reverse transcriptase (RT)-PCR was used to assess the expression of 30 key genes; microarray analyses were carried out on 25 tumours to identify a prognostic gene expression profile, with 13 blinded samples used to validate the identified profile. RESULTS: No gene was found to correlate with response by RT-PCR. The microarray analysis identified a gene expression profile of 28 genes, with 12 upregulated in the pCR group and 16 upregulated in non-pCR. The leave-one-out cross-validation test exhibited 72% accuracy, 86% specificity, and 55% sensitivity. The 28-gene expression profile classified the 13 validation samples with 92% accuracy, 89% specificity, and 100% sensitivity. CONCLUSION: Our results suggest that genes not involved in classical cancer pathways such as apoptosis or DNA repair could be involved in responses to a trastuzumab-docetaxel-based regimen. They also describe for the first time a gene expression signature that predicts trastuzumab response.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Perfilación de la Expresión Génica , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/genética , Docetaxel , Femenino , Humanos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor ErbB-2/análisis , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Taxoides/administración & dosificación , TrastuzumabRESUMEN
Survivin, a member of the inhibitory apoptosis protein family, gives rise, by an alternative splicing, to four variants with different functions. Many experimental studies indicate that p53 can regulate the expression of survivin and some of its splice variants. Although both the expression of survivin splice variants and the p53 gene were frequently altered in human cancers, nothing is known about their interactions in in vivo tumour samples. Here, we report that, in 162 breast carcinomas, p53 mutations are significantly associated with an increased expression of survivin and, in particular, its antiapoptotic splice variants (survivin-DeltaEx3 and survivin-3B). The upregulation of these variant expressions is particularly related to p53 mutations occurring in the residues belonging to the tetramerization domain. The loss of heterozygosity in the p53 gene is also associated with an increased expression of the survivin-DeltaEx3 variant. The expression of the proapoptotic variants (survivin-2B and survivin-2alpha) is not affected by any of these alterations. Our results provide for the first time in vivo evidence that, in human breast cancer, the survivin expression as well as its splicing depends on the p53 status. The results also suggest that the upregulation of antiapoptotic survivin variant expression by the mutant p53 may increase breast cancer cells survival and resistance to therapy.