甘草查尔酮B抑制膀胱肿瘤细胞生长及转移作用研究
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摘要
目的：研究甘草查尔酮B(Licochalcone B,LCB)对膀胱肿瘤细胞生长抑制及转移能力的影响,并阐明其作用机制,为甘草查尔酮B治疗膀胱肿瘤的临床应用提供理论依据。
方法：四甲基偶氮唑盐实验(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide,MTT)测定甘草查尔酮B对T24、EJ细胞生长的抑制效应；Hoechst荧光染色观察细胞形态变化；流式细胞技术检测甘草查尔酮B对细胞周期和细胞凋亡率影响；实时定量PCR(Real-time quantitative PCR, qRT-PCR)检测甘草查尔酮B对细胞周期相关蛋白在mRNA水平的影响；Westernblot检测甘草查尔酮B对细胞分裂周期蛋白(CDC25A,CDC25B),以及凋亡相关蛋白Bcl-2,Bax,Caspase-3,PARP和Survivin表达的影响；采用MTT法检测甘草查尔酮B对T24细胞与基质粘附能力的影响；划痕试验测定甘草查尔酮B对T24细胞体外迁移能力的影响；采用qRT-PCR.明胶酶谱两种方法测定甘草查尔酮B对细胞基质金属蛋白酶(MMP-2,MMP-9)表达的影响；酶联免疫法(ELISA)检测甘草查尔酮B对激活蛋白-1(AP-1)、核转录因子(NF-κB)表达的影响。建立C57BL/6小鼠皮下膀胱癌模型,分离肿瘤组织,利用HE染色和Tunnel法检测甘草查尔酮B对膀胱肿瘤的体内抑瘤作用。
结果：(1)经不同浓度(0,10,20,40,60,80μM)甘草查尔酮B分别处理24h,48h和72h,T24、EJ细胞增殖活力降低,当甘草查尔酮B浓度增加到20μM以上时(40,60,80μM)细胞增殖率明显低于对照组,呈浓度及时间依赖性变化；72h尤为明显,ICso分别为39.18±0.51μM,34.15±0.36μM。
(2)T24和EJ细胞经不同浓度甘草查尔酮B处理72h后,甘草查尔酮B能够诱导肿瘤细胞S期阻滞；降低S期相关周期蛋白(cyclinA)及蛋白激酶(CDK1,CDK2)的mRNA表达；降低S期相关细胞分裂周期蛋白Cdc25A.Cdc25B在蛋白水平的表达。
(3)不同浓度甘草查尔酮B处理T24和EJ细胞72h后,能够诱导细胞凋亡；下调Bcl-2表达,上调Bax和Caspase-3在蛋白水平上的表达,裂解PARP蛋白；并且在整体动物水平上能够抑制鼠膀胱肿瘤细胞增殖,诱导凋亡
(4)不同浓度甘草查尔酮B处理T24细胞24h后,细胞与基质间粘附力降低；与对照组相比,甘草查尔酮B显著降低MMP-9在mRNA及蛋白水平的表达,但对MMP-2表达无明显影响；能显著抑制NF-1cB表达,但对AP-1表达无明显影响。
结论：以上研究结果说明,甘草查尔酮B具有抑制膀胱肿瘤细胞生长和转移的作用,是一种有应用前景的膀胱肿瘤灌注药物。
Objective:To examine the mechanisms by which licochalcone B (LCB) inhibits the proliferation and metastasis of bladder cancer.
Methods:Cell viability was evaluated using a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The apoptotic rate was determined via flow cytometry using an annexin V-FITC apoptosis detection kit. The expressions of Bcl-2, Bax, caspase-3, survivin, poly (ADP-ribose) polymerase (PARP), cell division cycle25A (Cdc25A) and cell division cycle25B (Cdc25B) in protein level were analyzed via Western blot. The changes in mRNA level of cyclinA, cyclin-dependent kinase-1(CDK1) and cyclin-dependent kinase-2(CDK2) were detected by real-time quantitative PCR (qRT-PCR) assay. Cell-matrix adhesion of T24cells was measured through MTT assay. The migration of T24cells was measured by wound healing assay. The matrix metalloproteinase (MMP-2and MMP-9) activity in T24cells was measured by qRT-PCR and gelatin zymography methods. In addition, tumorigenicity, HE staining, and TUNEL staining were employed to investigate the influence of LCB on the growth of murine bladder cancer in vivo. The expressions of activator protein-1(AP-1) and nuclear factor-KB (NF-κB) were analyzed via enzyme-linked immunosorbent assay (ELISA).
Results:(1) The Findings indicated that LCB (40,60,80μM) significantly inhibited proliferation of bladder cancer T24and EJ cells in a concentration-and time-dependent manner.(2) LCB significantly induced cell cycle arrest in the S phase after72h of treatment and caused a decrease in cyclin A, CDK1, CDK2mRNA expressions accompanied with a decrease in Cdc25A and Cdc25B protein levels.(3) Hoechst dye staining of condensed nuclei and annexin V-FITC/PI staining revealed the manifestation of apoptosis after LCB-treated for72h. LCB treatment downregulated Bcl-2and survivin expressions, enhanced Bax expression, activated caspase-3and cleaved PARP protein. Consistently, the tumorigenicity of LCB-treated bladder cancer MB49cells was limited significantly in vitro and the MB49tumor model performed in C57BL/6mice in vivo.
(4) LCB signifieantly inhibited cell-matrix adhesion and decreased the MMP-9mRNA and protein expressions after LCB-treated T24cells for24h, as well as NF-κB level.
Conclusions:These findings provide support for the use of LCB in chemoprevention and bladder cancer therapy.
方法：四甲基偶氮唑盐实验(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide,MTT)测定甘草查尔酮B对T24、EJ细胞生长的抑制效应；Hoechst荧光染色观察细胞形态变化；流式细胞技术检测甘草查尔酮B对细胞周期和细胞凋亡率影响；实时定量PCR(Real-time quantitative PCR, qRT-PCR)检测甘草查尔酮B对细胞周期相关蛋白在mRNA水平的影响；Westernblot检测甘草查尔酮B对细胞分裂周期蛋白(CDC25A,CDC25B),以及凋亡相关蛋白Bcl-2,Bax,Caspase-3,PARP和Survivin表达的影响；采用MTT法检测甘草查尔酮B对T24细胞与基质粘附能力的影响；划痕试验测定甘草查尔酮B对T24细胞体外迁移能力的影响；采用qRT-PCR.明胶酶谱两种方法测定甘草查尔酮B对细胞基质金属蛋白酶(MMP-2,MMP-9)表达的影响；酶联免疫法(ELISA)检测甘草查尔酮B对激活蛋白-1(AP-1)、核转录因子(NF-κB)表达的影响。建立C57BL/6小鼠皮下膀胱癌模型,分离肿瘤组织,利用HE染色和Tunnel法检测甘草查尔酮B对膀胱肿瘤的体内抑瘤作用。
结果：(1)经不同浓度(0,10,20,40,60,80μM)甘草查尔酮B分别处理24h,48h和72h,T24、EJ细胞增殖活力降低,当甘草查尔酮B浓度增加到20μM以上时(40,60,80μM)细胞增殖率明显低于对照组,呈浓度及时间依赖性变化；72h尤为明显,ICso分别为39.18±0.51μM,34.15±0.36μM。
(2)T24和EJ细胞经不同浓度甘草查尔酮B处理72h后,甘草查尔酮B能够诱导肿瘤细胞S期阻滞；降低S期相关周期蛋白(cyclinA)及蛋白激酶(CDK1,CDK2)的mRNA表达；降低S期相关细胞分裂周期蛋白Cdc25A.Cdc25B在蛋白水平的表达。
(3)不同浓度甘草查尔酮B处理T24和EJ细胞72h后,能够诱导细胞凋亡；下调Bcl-2表达,上调Bax和Caspase-3在蛋白水平上的表达,裂解PARP蛋白；并且在整体动物水平上能够抑制鼠膀胱肿瘤细胞增殖,诱导凋亡
(4)不同浓度甘草查尔酮B处理T24细胞24h后,细胞与基质间粘附力降低；与对照组相比,甘草查尔酮B显著降低MMP-9在mRNA及蛋白水平的表达,但对MMP-2表达无明显影响；能显著抑制NF-1cB表达,但对AP-1表达无明显影响。
结论：以上研究结果说明,甘草查尔酮B具有抑制膀胱肿瘤细胞生长和转移的作用,是一种有应用前景的膀胱肿瘤灌注药物。
Objective:To examine the mechanisms by which licochalcone B (LCB) inhibits the proliferation and metastasis of bladder cancer.
Methods:Cell viability was evaluated using a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The apoptotic rate was determined via flow cytometry using an annexin V-FITC apoptosis detection kit. The expressions of Bcl-2, Bax, caspase-3, survivin, poly (ADP-ribose) polymerase (PARP), cell division cycle25A (Cdc25A) and cell division cycle25B (Cdc25B) in protein level were analyzed via Western blot. The changes in mRNA level of cyclinA, cyclin-dependent kinase-1(CDK1) and cyclin-dependent kinase-2(CDK2) were detected by real-time quantitative PCR (qRT-PCR) assay. Cell-matrix adhesion of T24cells was measured through MTT assay. The migration of T24cells was measured by wound healing assay. The matrix metalloproteinase (MMP-2and MMP-9) activity in T24cells was measured by qRT-PCR and gelatin zymography methods. In addition, tumorigenicity, HE staining, and TUNEL staining were employed to investigate the influence of LCB on the growth of murine bladder cancer in vivo. The expressions of activator protein-1(AP-1) and nuclear factor-KB (NF-κB) were analyzed via enzyme-linked immunosorbent assay (ELISA).
Results:(1) The Findings indicated that LCB (40,60,80μM) significantly inhibited proliferation of bladder cancer T24and EJ cells in a concentration-and time-dependent manner.(2) LCB significantly induced cell cycle arrest in the S phase after72h of treatment and caused a decrease in cyclin A, CDK1, CDK2mRNA expressions accompanied with a decrease in Cdc25A and Cdc25B protein levels.(3) Hoechst dye staining of condensed nuclei and annexin V-FITC/PI staining revealed the manifestation of apoptosis after LCB-treated for72h. LCB treatment downregulated Bcl-2and survivin expressions, enhanced Bax expression, activated caspase-3and cleaved PARP protein. Consistently, the tumorigenicity of LCB-treated bladder cancer MB49cells was limited significantly in vitro and the MB49tumor model performed in C57BL/6mice in vivo.
(4) LCB signifieantly inhibited cell-matrix adhesion and decreased the MMP-9mRNA and protein expressions after LCB-treated T24cells for24h, as well as NF-κB level.
Conclusions:These findings provide support for the use of LCB in chemoprevention and bladder cancer therapy.
引文
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