RESUMEN
Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1α and NF-κB. Since HSP90 activates HIF-1α and NF-κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1α and NF-κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50 nM for 24 h inhibited EMT (downregulated vimentin and upregulated E-cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF-1α or NF-κB resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our data demonstrate for the first time that inhibition of HSP90 downregulates both HIF-1α and NF-κB leading to inhibition of EMT, motility, and invasiveness in colorectal cancer.
Asunto(s)
Movimiento Celular/genética , Neoplasias Colorrectales/genética , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Proteínas HSP90 de Choque Térmico/genética , Invasividad Neoplásica/genética , Animales , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/fisiología , Colágeno/genética , Neoplasias Colorrectales/patología , Regulación hacia Abajo/genética , Combinación de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células HCT116 , Células HT29 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Laminina/genética , Ratones , Ratones Desnudos , FN-kappa B/genética , Invasividad Neoplásica/patología , Proteoglicanos/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Regulación hacia Arriba/genética , Vimentina/genéticaRESUMEN
PURPOSE: Colorectal cancer has a distinct clinicopathologic presentation in younger patients. The aim of this paper was to evaluate the outcome of younger (age below 50 y) and older patients with stage IV (advanced) colorectal cancer in the modern era of combination chemotherapy. METHODS: Cases of metastatic colorectal cancer reported in Surveillance, Epidemiology, and End Results registry (1973 to 2008) were reviewed. Demographics, tumor characteristics, and overall and cancer-specific survivals in patients below 50 and above 50 years of age were compared by Cox proportional hazard analyses. Joinpoint regression analysis was used to evaluate secular trends in 2-year survival. RESULTS: Younger patients had a greater proportion of negative clinicopathologic features (male sex, African American ethnicity, and signet ring or mucinous histology). In multivariate analysis, older age, male sex, African American ethnicity, right-sided tumors, and signet ring histology were associated with higher mortality risk. Younger patients had improved survival (hazard ratio 0.72; 95% confidence interval: 0.70-0.75) compared with older patients, whereas all patients experienced increased 2-year survival by joinpoint analysis beginning in 1999-2000. CONCLUSIONS: The results confirm decreased mortality from advanced colorectal cancer in the era of modern combination chemotherapy in younger and older patients. Younger age, non-right-sided tumors, and absence of signet ring histology significantly associate with better survival.