组蛋白脱乙酰酶抑制剂丁酸钠对胰腺癌细胞53-kDa蛋白表达及抗癌药物敏感性的影响
Effects of a histone deacetylase inhibitor, sodium butyrate, on 53-kDa protein expression and sensitivity to anticancer drugs of pancreatic cancer cells.
作者信息
Kitazono Masaki, Shinchi Hiroyuki, Ishigami Sumiya, Ueno Shinichi, Natsugoe Shoji
机构信息
Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School, Kagoshima, Japan.
出版信息
Curr Ther Res Clin Exp. 2010 Jun;71(3):162-72. doi: 10.1016/j.curtheres.2010.06.002.
BACKGROUND
Several tumor-suppressor genes, such as 53-kDa protein (p53), are inactivated in some pancreatic cancers. The lack of a functional p53 has been proposed to be a component of resistance to chemotherapy, resulting in the inhibition of apoptosis. Therefore, reintroduction of wild-type p53 is a commonly used gene therapy strategy for the treatment of various types of cancer, including pancreatic cancer.
OBJECTIVE
The aim of this study was to examine the ability of the histone deacetylase inhibitor, sodium butyrate (NaB), to modulate the expression of p53.
METHODS
Five human pancreatic carcinoma cell lines (SW-1990, BxPC-3, PANC-1, MIA PaCa-2, JHP-1) were utilized. Two of the cell lines (SW-1990 and JHP-1) lacked p53 expression, as determined by Western blot analysis, and were investigated further. Expression of p53 was determined by densitometry of all bands present in the Western blot. Drug sensitivity was measured with a tetrazolium-based assay by exposing the cells to graded concentrations of NaB and/or anticancer drugs (cisplatin, fluorouracil, SN-38, and paclitaxel). Apoptosis was observed using gel electrophoresis.
RESULTS
In the SW-1990 and JHP-1 cell lines, use of 1 mM NaB was found to induce histone acetylation and p53 expression compared with those not treated with NaB (P = 0.01 and P = 0.018, respectively). Sensitivity to cisplatin (P = 0.021), fluorouracil (P = 0.046), and SN-38 (P = 0.039) was significantly enhanced by NaB treatment compared with nontreatment. However, sensitivity to paclitaxel was not significantly different between untreated and NaB-treated cells. A higher frequency of apoptosis was observed in NaB-treated cells compared with that of control cells.
CONCLUSION
This in vitro study found that NaB induced p53 expression in 2 pancreatic cancer cell lines (SW-1990 and JHP-1). Moreover, NaB acted on a biochemical modulator for antieuplastic therapy. Future research is necessary to assess the value of these findings.
背景
一些肿瘤抑制基因，如53-kDa蛋白（p53），在某些胰腺癌中失活。有人提出缺乏功能性p53是化疗耐药的一个因素，导致细胞凋亡受到抑制。因此，重新引入野生型p53是治疗包括胰腺癌在内的各种癌症常用的基因治疗策略。
目的
本研究旨在检测组蛋白脱乙酰酶抑制剂丁酸钠（NaB）调节p53表达的能力。
方法
使用5种人胰腺癌细胞系（SW-1990、BxPC-3、PANC-1、MIA PaCa-2、JHP-1）。通过蛋白质印迹分析确定，其中2种细胞系（SW-1990和JHP-1）缺乏p53表达，并对其进行进一步研究。通过对蛋白质印迹中所有条带进行光密度测定来确定p53的表达。通过将细胞暴露于不同浓度的NaB和/或抗癌药物（顺铂、氟尿嘧啶、SN-38和紫杉醇），采用基于四氮唑的检测方法测量药物敏感性。使用凝胶电泳观察细胞凋亡。
结果
在SW-1990和JHP-1细胞系中，发现与未用NaB处理的细胞相比，使用1 mM NaB可诱导组蛋白乙酰化和p53表达（分别为P = 0.01和P = 0.018）。与未处理相比，NaB处理显著增强了对顺铂（P = 0.（此处原文有误，应为0.021））、氟尿嘧啶（P = 0.046）和SN-38（P = 0.039）的敏感性。然而，未处理细胞和NaB处理细胞对紫杉醇的敏感性无显著差异。与对照细胞相比，在NaB处理的细胞中观察到更高频率的细胞凋亡。
结论
这项体外研究发现，NaB可诱导2种胰腺癌细胞系（SW-1990和JHP-1）中的p53表达。此外，NaB可作为抗肿瘤治疗的生化调节剂。有必要进行进一步研究以评估这些发现的价值。
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