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].
KYA1797K 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CRC cells
25 µM
3 to 7 days
Effectively suppressed the stemness of CSCs
Cell Commun Signal. 2020 Mar 6;18(1):38.
TNBC cells
5 or 25 µM
24 hours
KYA1797K downregulates β-catenin, RAS, and EGFR and suppresses proliferation and colony formation.
Exp Mol Med. 2020 May;52(5):832-842.
KYA1797K 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Athymic nu/nu mice
Tumor xenograft model
Intraperitoneal injection
20 mg/kg
Once daily for 21 days
To test the effect of KYA1797K on tumor growth, results showed that KYA1797K significantly reduced tumor volume and weight.
Exp Mol Med. 2018 Nov 20;50(11):1-12
Mice
ApcMin/+ /KrasG12DLA2 mice
Intraperitoneal injection
25 mg/kg
5 days per week for 7 weeks
Suppressed tumor growth and reduced stemness of CSCs
Cell Commun Signal. 2020 Mar 6;18(1):38.
Mice
TNBC PDX tumors
Intraperitoneal injection
25 mg/ml
Daily until tumor size reached between 150 and 200 mm3
KYA1797K suppressed the growth of TNBC PDX tumors.
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