RESUMEN
BACKGROUND: Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown. METHODS: Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulations (ALDH(+)/CD133(+)). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined. RESULTS: Our results observed that ALDH(+)/CD133(+) colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model. CONCLUSION: Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer.
Asunto(s)
Derivados del Benceno/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Curcumina/análogos & derivados , Cetonas/uso terapéutico , Células Madre Neoplásicas/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacología , Carcinoma/patología , Línea Celular Tumoral , Neoplasias del Colon/patología , Curcumina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Femenino , Células HCT116 , Células HT29 , Humanos , Cetonas/administración & dosificación , Cetonas/farmacología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new enantiocontrolled synthesis of a potent immunosuppressant(-)-mycestericin E has been accomplished by using cinchona alkaloid-catalyzed asymmetric Baylis-Hillman reaction of an aldehyde with 1,1,1,3,3,3-hexafluoroisopropyl acrylate and Lewis acid-promoted cyclisation of an epoxytrichloroacetimidate as the key steps.
Asunto(s)
Acrilamida/química , Aldehídos/química , Alcaloides de Cinchona/química , Ácidos Grasos Monoinsaturados/síntesis química , Catálisis , Ácidos Grasos Monoinsaturados/química , Cinética , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , Extractos Vegetales , Estereoisomerismo , TermodinámicaRESUMEN
The Hic-5 protein is encoded by a transforming growth factor-beta1- and hydrogen peroxide-inducible gene, hic-5, and has striking similarity to paxillin, especially in their C-terminal LIM domains. Like paxillin, Hic-5 is localized in focal adhesion plaques in association with focal adhesion kinase in cultured fibroblasts. We carried out yeast two-hybrid screening to identify cellular factors that form a complex with Hic-5 using its LIM domains as a bait, and we identified a cytoplasmic tyrosine phosphatase (PTP-PEST) as one of the partners of Hic-5. These two proteins are associated in mammalian cells. From in vitro binding experiments using deletion and point mutations, it was demonstrated that the essential domain in Hic-5 for the binding was LIM 3. As for PTP-PEST, one of the five proline-rich sequences found on PTP-PEST, Pro-2, was identified as the binding site for Hic-5 in in vitro binding assays. Paxillin also binds to the Pro-2 domain of PTP-PEST. In conclusion, Hic-5 may participate in the regulation of signaling cascade through its interaction with distinct tyrosine kinases and phosphatases.