CXCL12-CXCR4 信号轴赋予胰腺癌细胞对吉西他滨的耐药性：一种新的治疗靶点。

CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy.

机构信息

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama 36604-1405, USA.

出版信息

Br J Cancer. 2010 Nov 23;103(11):1671-9. doi: 10.1038/sj.bjc.6605968. Epub 2010 Nov 2.

BACKGROUND

Pancreatic cancer cells are highly resistant to drug therapy; however, underlying causes remain largely unknown. We hypothesised that the activation of CXCL12-CXCR4 signalling confers drug resistance to pancreatic cancer cells by potentiating survival. CXCR4 is overexpressed in precancerous/malignant pancreatic lesions and cancer stem cells, and implicated in its pathogenesis.

METHODS

Effect of CXCR4 activation by CXCL12 on restricting the gemcitabine-induced cytotoxicity and stimulating the survival signalling was examined in pancreatic cancer cells by MTT, DNA laddering, caspase activity, immunoblot, and promoter-reporter assays. Subsequently, we examined the effect of CXCR4 antagonist, AMD3100, in abrogating the rescue effect of activated CXCL12-CXCR4 signalling.

RESULTS

The pancreatic cancer cells treated with gemcitabine exhibited reduced cytotoxicity in the presence of CXCL12 as compared with the cells treated with drug alone. CXCL12 induced the activation of FAK, ERK, and Akt signalling pathways, enhanced transcriptional activities of β-catenin and NF-κB, and expression of survival proteins. AMD3100 arrested the CXCL12-induced pancreatic cancer cell growth and drug resistance.

CONCLUSION

Our findings demonstrate, for the first time, a role of CXCL12-CXCR4 signalling axis in conferring drug resistance to pancreatic cancer cells and suggest that it could serve as a novel therapeutic target for pancreatic cancer therapy, alone and in combination with the cytotoxic drug.

背景

胰腺癌细胞对药物治疗具有高度抗性；然而，其潜在原因在很大程度上尚不清楚。我们假设，CXCL12-CXCR4 信号的激活通过增强存活能力赋予胰腺癌细胞耐药性。CXCR4 在癌前/恶性胰腺病变和癌症干细胞中过表达，并与发病机制有关。

方法

通过 MTT、DNA 梯状带、半胱天冬酶活性、免疫印迹和启动子报告基因分析，研究了 CXCL12 对胰腺癌细胞中 CXCR4 激活对限制吉西他滨诱导的细胞毒性和刺激存活信号的影响。随后，我们研究了 CXCR4 拮抗剂 AMD3100 对消除激活的 CXCL12-CXCR4 信号的挽救作用的影响。

结果

与单独用药物处理的细胞相比，用吉西他滨处理的胰腺癌细胞在存在 CXCL12 的情况下表现出降低的细胞毒性。CXCL12 诱导 FAK、ERK 和 Akt 信号通路的激活，增强 β-连环蛋白和 NF-κB 的转录活性以及存活蛋白的表达。AMD3100 阻止了 CXCL12 诱导的胰腺癌细胞生长和耐药性。