Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin.
Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin.
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DOI：
10.1371/journal.pone.0004054
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Ju J
中科院分区：
文献类型：
--
作者：
Gavin EJ;Song B;Wang Y;Xi Y;Ju J
我们小组先前的研究表明，在结直肠癌患者标本中Orc 6的表达水平高度升高，并且Orc 6的诱导与5-氟尿嘧啶（5-FU）治疗相关。本研究的目的是研究Orc 6在结肠癌中的分子和细胞影响。在这项研究中，我们使用HCT 116（wt-p53）和HCT 116（null-p53）结肠癌细胞系作为模型系统，研究Orc 6对细胞增殖，化疗敏感性和与Orc 6相关的通路的影响。我们证明了Orc 6的下调使结肠癌细胞对5-FU和顺铂（cis-pt）治疗敏感。通过RNA干扰降低HCT-116（wt-p53）细胞中Orc 6的表达，触发细胞周期停滞在G1期。在HCT-116（wt-p53）细胞系中，长时间抑制Orc 6表达导致多核细胞。Western免疫印迹分析显示，下调Orc 6可诱导HCT-116（wt-p53）细胞p21表达。p21的诱导是由p53在ser-15磷酸化水平的增加介导的。相比之下，HCT-116（null-p53）细胞中p21的表达没有升高。Orc 6的下调还增加了DNA损伤修复蛋白GADD 45 β的表达，降低了JNK 1的表达水平。orc 6可能是一个潜在的新靶点，为未来的结肠癌抗癌治疗的发展。
Previous studies from our group have shown that the expression levels of Orc6 were highly elevated in colorectal cancer patient specimens and the induction of Orc6 was associated with 5-fluorouracil (5-FU) treatment. The goal of this study was to investigate the molecular and cellular impact of Orc6 in colon cancer. In this study, we use HCT116 (wt-p53) and HCT116 (null-p53) colon cancer cell lines as a model system to investigate the impact of Orc6 on cell proliferation, chemosensitivity and pathways involved with Orc6. We demonstrated that the down regulation of Orc6 sensitizes colon cancer cells to both 5-FU and cisplatin (cis-pt) treatment. Decreased Orc6 expression in HCT-116 (wt-p53) cells by RNA interference triggered cell cycle arrest at G1 phase. Prolonged inhibition of Orc6 expression resulted in multinucleated cells in HCT-116 (wt-p53) cell line. Western immunoblot analysis showed that down regulation of Orc6 induced p21 expression in HCT-116 (wt-p53) cells. The induction of p21 was mediated by increased level of phosphorylated p53 at ser-15. By contrast, there is no elevated expression of p21 in HCT-116 (null-p53) cells. Orc6 down regulation also increased the expression of DNA damaging repair protein GADD45β and reduced the expression level of JNK1. Orc6 may be a potential novel target for future anti cancer therapeutic development in colon cancer.
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