Colorectal cancer (CRC) is one of the most frequent cancers and the second leading cause of cancer-related deaths in Western countries. Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. KYA1797K selectively regulates the Wnt/β-catenin and Ras/ERK pathways. YA1797K inhibited TOPflash activity to a greater extent with an IC50 of 0.75 μM, and effectively reduced the levels of both β-catenin and pan-Ras as well as the activities of ERK (extracellular-signal-regulated kinase) and Akt in SW480 cells. Using multipathway reporter arrays, KYA1797K significantly (P < 0.01) decreased reporter activities for the Wnt/β-catenin and MAPK/ERK pathways. In the CRC lines SW480, LoVo, DLD1 and HCT15, KYA1797K degraded both β-catenin and Ras in a dose-dependent manner. Consistently, cell proliferation was suppressed by KYA1797K treatment. KYA1797K destabilized β-catenin and Ras in DLD1 cells expressing WT β-catenin or WT K-Ras. Those data indicated that KYA1797K inhibited proliferation of CRC cells mainly via destabilization of β-catenin with additional Ras degradation. In vivo, KYA1797K was injected intraperitoneally (i.p.) into mice carrying xenografted tumors from the D-MT cell line that harbors both APC and KRAS mutations. KYA1797K administration (25 mg/kg) reduced both weight and volume of the tumor by 70%. KYA1797K treatment significantly reduced levels of β-catenin and Ras proteins as well as Wnt/β-catenin and Ras signaling target[2].
作用机制
KYA1797K bound directly to the regulators of G-protein signaling domain of axin[2].
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