KW-2478对结直肠癌细胞增殖的抑制作用及其机制OACSTPCD

OBJECTIVE:To investigate effect and underlying mechanism of HSP90α inhibitor KW-2478 on malignant phenotypes of colorectal cancer(CRC)cells.METHODS:Using DMSO as solvent control,colorectal cancer cells RKO and DLD1 were treated with different concentrations of KW-2478.The proliferation rate of colorectal cancer cells was detected by CCK8 kit;the colony formation rate was detected by plate colony formation assay;flow cytometry was used to analyze the cell cycle;Western blot was used to detect the expression level and phosphorylation level of proliferation and cycle regulation-related proteins.RESULTS:Compared with the control group,the proliferation capacity of RKO cells treated with 0.8 μmol/L KW-2478 and DLD1 cells treated with 40 μmol/L KW-2478 decreased by more than 50％,and the IC50 of both cells were(0.5±1.2)μmol/L and(40.0±3.1)μmol/L,respectively.After treatment with KW-2478,the sum colony formation rate of both cells were reduced by more than 40％when compared with the control group(P<0.01).Meanwhile,KW-2478 significantly induced G2/M phase arrest(P<0.01).Upon KW-2478 treatment,the protein abundance of HSP90a client proteins EGFR,AKT and S6,and the phosphorylation levels of AKT,ERK and S6 were reduced,while the expressions of mitosis-specific marker p-Histone H3 and Cyclin B1 protein were upregulated.CONCLUSION:KW-2478 significantly inhibited the proliferation viability and colony formation ability of RKO and DLD1 and induced markedly G2/M phase arrest.The observed effects may be related to inhibiting the activity of EGFR-related signaling pathways and upregulating the expression of cycle-related proteins.