Lou Debao, Zhu Lina, Ding Huawei, Dai Hai-Yan, Zou Gang-Ming
Department of Pharmacy, Shanghai Eighth People's Hospital, Shanghai 200235, P.R. China.
Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China.
Oncol Lett. 2014 Apr;7(4):1078-1082. doi: 10.3892/ol.2014.1864. Epub 2014 Feb 10.
Ape1 is an important redox protein, essential for specific cytokine-induced signal transduction. Ape1 signaling is also important in regulating the growth of cancer cells, including colon cancer cells. The present study investigated whether Ape1 signaling plays a role in the regulation of colon cancer stem cell (CCSC) growth. The results showed that Ape1 was aberrantly expressed in CCSCs, as determined by quantitative (q)PCR assay. A laser confocal microscopy assay demonstrated that the Ape1 protein was mainly distributed in the nuclei, but not the cytoplasm, of the CSCs. Treatment of CCSCs with Ape1 redox inhibitor (E3330) significantly affected growth . In colon cancer xenograft mice, administration of E3330 enhanced tumor responses to the chemotherapeutic drug, 5-fluorouracil (5-FU). Furthermore, the combination of E3330 and 5-FU evidently increased the cytotoxicity of 5-FU in CSC growth. In the qPCR assay, the CCSCs were demonstrated to express the dominant ATP-binding cassette sub-family G member 2 (ABC-G2), but not the multidrug resistance 1, genes. Thus, we hypothesized that drug resistance in CCSCs is mediated by ABC-G2. Since CSCs are involved in cancer metastasis, the Ape1 inhibitor may be a potential agent in the inhibition of colon cancer growth and metastasis.
Ape1是一种重要的氧化还原蛋白，对特定细胞因子诱导的信号转导至关重要。Ape1信号传导在调节癌细胞（包括结肠癌细胞）的生长中也很重要。本研究调查了Ape1信号传导是否在调节结肠癌干细胞（CCSC）生长中发挥作用。结果表明，通过定量（q）PCR分析确定，Ape1在CCSC中异常表达。激光共聚焦显微镜分析表明，Ape1蛋白主要分布在CSC的细胞核中，而非细胞质中。用Ape1氧化还原抑制剂（E3330）处理CCSC显著影响其生长。在结肠癌异种移植小鼠中，给予E3330增强了肿瘤对化疗药物5-氟尿嘧啶（5-FU）的反应。此外，E3330和5-FU的联合明显增加了5-FU对CSC生长的细胞毒性。在qPCR分析中，CCSC被证明表达主要的ATP结合盒亚家族G成员2（ABC-G2），但不表达多药耐药1基因。因此，我们假设CCSC中的耐药性是由ABC-G2介导的。由于CSC参与癌症转移，Ape1抑制剂可能是抑制结肠癌生长和转移的潜在药物。
