Decreased FANCJ caused by 5FU contributes to the increased sensitivity to oxaliplatin in gastric cancer cells.
Decreased FANCJ caused by 5FU contributes to the increased sensitivity to oxaliplatin in gastric cancer cells.
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DOI：
10.1007/s10120-012-0191-0
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发表时间：
2013-07
期刊：
影响因子：
7.4
通讯作者：
Yasui, Wataru
中科院分区：
文献类型：
--
作者：
Mori, Ryutaro;Yoshida, Kazuhiro;Tanahashi, Toshiyuki;Yawata, Kazunori;Kato, Junko;Okumura, Naoki;Tsutani, Yasuhiro;Okada, Morihito;Oue, Naohide;Yasui, Wataru
奥沙利铂对多种类型的癌症有效，5-氟尿嘧啶（5 FU）和奥沙利铂的组合对胃癌以及结肠癌具有协同作用。FANCJ蛋白是范可尼贫血（FA）基因产物之一，其与肿瘤抑制因子BRCA 1的相互作用是DNA双链断裂（DSB）修复所必需的。FANCJ还通过连接错配修复蛋白复合物MLH 1-PMS 2（MutLα）在链间交联（ICL）修复中发挥作用。虽然奥沙利铂引起ICL，但认为5 FU引起DSB。因此，我们研究了FANCJ在奥沙利铂和5 FU在MKN 45胃癌细胞和衍生的5 FU耐药细胞系MKN 45/F2 R中的协同作用中的重要性。用5 FU和/或奥沙利铂处理MKN 1、TMK 1、MKN 45和MKN 45/F2 R（5 FU-抗性）胃癌细胞。通过蛋白质印迹分析和逆转录聚合酶链反应（RT-PCR）评估信号通路。采用MTT法检测耐药性。在MKN 45细胞中，5 FU和奥沙利铂的组合具有协同作用。5 FU处理后出现DSB。FANCJ下调，BRCA 1以剂量和时间依赖性方式诱导。当FANCJ被短干扰（si）RNA敲低时，MKN 45细胞显示出对奥沙利铂的敏感性增加。然而，在MKN 45/F2 R 5 FU耐药细胞中未观察到这些发现。这些结果强烈表明，5 FU治疗引起的FANCJ减少导致对奥沙利铂的敏感性增加，从而表明FANCJ蛋白在5 FU和奥沙利铂联合用药的协同作用中发挥重要作用。
Oxaliplatin is effective against many types of cancer, and the combination of 5-fluorouracil (5FU) and oxaliplatin is synergistically effective against gastric cancer, as well as colon cancer. The FANCJ protein is one of the Fanconi anemia (FA) gene products, and its interaction with the tumor suppressor BRCA1 is required for DNA double-strand break (DSB) repair. FANCJ also functions in interstrand crosslinks (ICLs) repair by linking to mismatch repair protein complex MLH1-PMS2 (MutLα). While oxaliplatin causes ICLs, 5FU is considered to cause DSBs. Therefore, we investigated the importance of FANCJ in the synergistic effects of oxaliplatin and 5FU in MKN45 gastric cancer cells and the derived 5FU-resistant cell line, MKN45/F2R. MKN1, TMK1, MKN45, and MKN45/F2R (5FU-resistant) gastric cancer cells were treated with 5FU and/or oxaliplatin. The signaling pathway was evaluated by a western blotting analysis and reverse transcription polymerase chain reaction (RT-PCR). Drug resistance was evaluated by the 3-(4,5-dimethyl-2-tetrazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. In MKN45 cells, the combination of 5FU and oxaliplatin had synergistic effects. DSBs appeared when the cells were treated with 5FU. FANCJ was down-regulated, and BRCA1 was induced in a dose- and time-dependent manner. MKN45 cells showed increased sensitivity to oxaliplatin when FANCJ was knocked down by short interfering (si) RNA. However, these findings were not observed in MKN45/F2R 5FU-resistant cells. These results strongly suggest that the decrease in FANCJ caused by 5FU treatment leads to an increase in sensitivity to oxaliplatin, thus indicating that the FANCJ protein plays an important role in the synergism of the combination of 5FU and oxaliplatin.
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影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
影响因子：
9.7
作者：
Kachnic, Lisa A.;Li, Li;Willers, Henning
通讯作者：
Willers, Henning
影响因子：
3.4
作者：
Oh, Sung Yong;Kwon, Hyuk-Chan;Kang, Jung Hun
通讯作者：
Kang, Jung Hun
影响因子：
50.5
作者：
Koizumi, W.;Takiuchi, H.;Tsuburaya, A.
通讯作者：
Tsuburaya, A.
DOI：
10.1097/01.coc.0000221358.57089.f2
发表时间：
2006-08-01
影响因子：
2.6
作者：
Cavanna, Luigi;Artioli, Fabrizio;Zaniboni, Alberto
通讯作者：
Zaniboni, Alberto