RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells.
RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells.
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RFPL4A 增加人结直肠癌细胞的 G1 群体并降低对化疗的敏感性。
DOI：
10.1074/jbc.m114.614859
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发表时间：
2015
期刊：
影响因子：
4.8
通讯作者：
Naito et al.
中科院分区：
文献类型：
--
作者：
Hiraki M;Nishimura J;Takahashi H;Wu X;Takahashi Y;Miyo M;Nishida N;Uemura M;Hata T;Takemasa I;Mizushima T;Soh JW;Doki Y;Mori M;Yamamoto H.;Naito et al.
细胞周期停滞的癌细胞对作用于细胞周期的有丝分裂期的常规化疗具有抗性，尽管参与停止细胞周期进展的分子机制仍不清楚。在这里，我们证明了RFPL 4A，一种未知的泛素连接酶，诱导G1滞留，从而降低了人结肠直肠癌细胞系HCT 116对化疗的敏感性。在携带“基于荧光泛素的细胞周期指示剂”的HCT 116细胞中进行的长期时间推移观察确定了一个特征性群体，该群体是可行的，但在G1期保持较长的时间（长达56小时）。基因芯片分析显示RFPL4A的表达在这些G1期阻滞的细胞中显著上调，不仅在HCT 116细胞中，而且在其他癌细胞系中，RFPL4A的过表达增加了G1期细胞群，降低了对化疗的敏感性。然而，RFPL 4A表达的敲低导致细胞恢复有丝分裂，并诱导其对体外和体内抗癌药物的敏感性。这些结果表明，RFPL4A是一种新的因素，增加G1群体，降低化疗的敏感性，因此可能是一个有前途的治疗靶点难治性肿瘤条件。
Cell cycle-arrested cancer cells are resistant to conventional chemotherapy that acts on the mitotic phases of the cell cycle, although the molecular mechanisms involved in halting cell cycle progression remain unclear. Here, we demonstrated that RFPL4A, an uncharacterized ubiquitin ligase, induced G1retention and thus conferred decreased sensitivity to chemotherapy in the human colorectal cancer cell line, HCT116. Long term time lapse observations in HCT116 cells bearing a “fluorescence ubiquitin-based cell cycle indicator” identified a characteristic population that is viable but remains in the G1phase for an extended period of time (up to 56 h). Microarray analyses showed that expression of RFPL4A was significantly up-regulated in these G1-arrested cells, not only in HCT116 cells but also in other cancer cell lines, and overexpression of RFPL4A increased the G1population and decreased sensitivity to chemotherapy. However, knockdown of RFPL4A expression caused the cells to resume mitosis and induced their susceptibility to anti-cancer drugsin vitroandin vivo. These results indicate that RFPL4A is a novel factor that increases the G1population and decreases sensitivity to chemotherapy and thus may be a promising therapeutic target for refractory tumor conditions.