4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Colorectal-Neoplasms

Activin belongs to transforming growth factor (TGF)-β super family of growth and differentiation factors and activin pathway participated in broad range of cell process. Studies elaborated activin pathway maintain pluripotency in human stem cells and suggest that the function of activin/nodal signaling in self-renew would be conserved across embryonic and adult stem cells. In this study, we tried to determine the effect of activin signaling pathway in regulation of cancer stem cells as a potential target for cancer therapy in clinical trials. A population of colorectal cancer cells was selected by the treatment of activin A. This population of cell possessed stem cell character with sphere formation ability. We demonstrated activin pathway enhanced the colorectal cancer stem cells self-renew and contribute to colorectal cancer progression in vivo. Targeting activin pathway potentially provide effective strategy for colorectal cancer therapy.

Topics: Activin Receptors; Activins; Benzamides; Cell Self Renewal; Colorectal Neoplasms; Dioxoles; Disease Progression; HCT116 Cells; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Neoplastic Stem Cells

Disruptions to the TGFbeta signalling pathway have been implicated in most human adenocarcinomas. As cancers progress, many acquire resistance to the growth-suppressing properties of TGFbeta while retaining sensitivity to its tumour-promoting effects. Microsatellite unstable colorectal cancers (MSI-H CRCs) possess truncating mutations in the type II TGFbeta receptor (TGFbetaRII) gene that have been assumed to render these tumours insensitive to TGFbeta. However, numerous reports of TGFbetaRII bypass exist and this study was thus undertaken in order to clarify the true extent of TGFbeta sensitivity in MSI-H CRCs. Using stimulation with exogenous TGFbeta, we demonstrated that, while MSI-H CRCs are capable of binding soluble TGFbeta, two out of three cell lines examined remain refractory to its signalling effects. In contrast, use of a specific inhibitor of the type I TGFbeta receptor (TGFbetaRI) revealed that all remain sensitive to signalling by endogenously produced TGFbeta. Specifically, autocrine signalling via TGFbetaRI mediates constitutive activation of Smad2 as well as repression of Erk signalling. Real-time PCR confirmed that these effects are sufficient to affect the expression level of various TGFbeta-modulated genes. An invasion assay revealed that autocrine TGFbetaRI signalling also promotes the invasion capacity of MSI-H CRCs to an extent similar to that seen in their non-MSI-H counterparts. Independent TGFbetaRI signalling, however, has no effect on the rate of proliferation of MSI-H CRC cells. Together, these results demonstrate that MSI-H CRC cell lines are not completely refractory to TGFbeta, despite lacking functional TGFbetaRII. In addition to clarifying the true consequences of natural TGFbetaRII loss and the independent function of TGFbetaRI, our results highlight the selective nature of TGFbeta resistance developed by cancers.

Topics: Autocrine Communication; Benzamides; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Dioxoles; Drug Resistance, Neoplasm; Humans; Loss of Heterozygosity; Microsatellite Instability; Mutation; Protein Binding; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta