新的蛋白酶体抑制剂YSY-01A对HT-29细胞的周期阻滞作用

摘要

Compound YSY-01A,a recently synthesized proteasome inhibitor,has shown potent growth-inhibitory effect on tumor cells in previous researches.However,the mechanism of its inhibitory effects,especially on cell cycle,remains largely unclear.This study aims to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect,and to probe the possible molecular mechanisms for its effects on human colorectal adenocarcinoma cells HT-29.The results suggested that YSY-01A significantly (P＜0.05) inhibited cellular proliferation of HT-29 cells in a time and concentration-dependent manner.Furthermore,YSY-01A suppressed the G2/M transition of HT-29 cells,whereas the mitotic inhibitor paclitaxel induced M phase accumulation.Further investigation revealed that YSY-01A significantly (P＜0.05) up-regulated the expression levels of a series of cell cycle related protein,such as cyclin B1,Weel,p-cdc2 (Tyrl 5),p53,p21,and p27.The HT-29 cells only exhibited typical cytotoxic symptom when YSY-01A concentration reached 0.5 μM (P＜0.05),which was above the dose we used in the mechanism research.In conclusion,YSY-01A showed remarkable anti-cancer activity on HT-29 cells,and its molecular mechanisms are related to G2/M cell cycle transition arrest.%化合物YSY-01A是一种新合成的蛋白酶体抑制剂,前期研究已经证实其具有良好的抑制肿瘤增殖作用.但是其作用机制尤其是对细胞周期的阻滞作用仍不清楚.本实验旨在评价YSY-01A的抗肿瘤作用与细胞周期阻滞的关系,并探讨可能的分子机制.实验结果证实,YSY-01A能够显著抑制大肠腺癌细胞HT-29的增殖(P＜0.05),且具有浓度和时间依赖性.进一步实验表明,YSY-01A能够把HT-29细胞阻滞在G2/M转换点上,显著地上调cyclin B1,Weel,p-cdc2 (Tyrl5)及p53,p21,p27蛋白的表达(P＜0.05).当YSY-0lA浓度高于0.5 μM时,HT-29会显示出典型的细胞毒症状,差异具有显著性(P＜0.05)；而本文用于机制研究的药物浓度均低于此值.总之,YSY-01A对HT-29细胞具有显著的增殖抑制作用,其分子机制与G2/M转换点阻滞有关.