Zheng Chunning, Jiao Xuelong, Jiang Yingsheng, Sun Shaochuan
Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China.
J Int Med Res. 2013 Apr;41(2):300-6. doi: 10.1177/0300060512474128. Epub 2013 Feb 6.
To test the hypothesis that chemoresistance in pancreatic cancer is mediated via extracellular signal-regulated protein kinase (ERK) 1/2 overactivity.
The human pancreatic cancer cell lines BxPC3, PANC-1 and a stably gemcitabine-resistant subline, PANC1(GemRes), were treated with combinations of gemcitabine and the ERK1/2 inhibitor, U0126. Phosphorylated (p)ERK1/2 was examined by Western blotting; cell proliferation and apoptosis were quantified. A nude mouse xenograft model was established with each cell line, and the therapeutic efficacy of gemcitabine and U0126 alone or in combination was examined.
Gemcitabine treatment visibly increased pERK1/2 levels in BxPC-3 and PANC-1 cells. PANC-1(GemRes) constitutively produced high levels of pERK1/2. U0126 treatment reversed the gemcitabine-associated increase in cell proliferation and reduction in apoptosis, in all three cell lines. Combination treatment with U0126 and gemcitabine inhibited tumour growth and promoted apoptosis in xenograft tumours derived from all three cell lines.
ERK1/2 activity may protect pancreatic cancer cells from chemotherapy-induced apoptosis. The combined use of an ERK1/2 inhibitor (such as U0126) together with gemcitabine may result in synergistic therapeutic effects at tolerable gemcitabine doses.
验证胰腺癌的化疗耐药是通过细胞外信号调节蛋白激酶（ERK）1/2过度激活介导的这一假说。
用人胰腺癌细胞系BxPC3、PANC-1以及一个吉西他滨稳定耐药亚系PANC1（GemRes），用吉西他滨和ERK1/2抑制剂U0126联合处理。通过蛋白质免疫印迹法检测磷酸化（p）ERK1/2；对细胞增殖和凋亡进行定量分析。用每个细胞系建立裸鼠异种移植模型，检测吉西他滨和U0126单独或联合使用的治疗效果。
吉西他滨处理明显增加了BxPC-3和PANC-1细胞中pERK1/2的水平。PANC-1（GemRes）持续产生高水平的pERK1/2。U0126处理逆转了吉西他滨在所有三个细胞系中引起的细胞增殖增加和凋亡减少。U0126和吉西他滨联合处理抑制了来自所有三个细胞系的异种移植肿瘤的生长并促进了凋亡。
ERK1/2活性可能保护胰腺癌细胞免受化疗诱导的凋亡。在可耐受的吉西他滨剂量下，将ERK1/2抑制剂（如U0126）与吉西他滨联合使用可能会产生协同治疗效果。
