Evans Jonathan P, Winiarski Boleslaw K, Sutton Paul A, Jones Robert P, Ressel Lorenzo, Duckworth Carrie A, Pritchard D Mark, Lin Zhi-Xiu, Fretwell Vicky L, Tweedle Elizabeth M, Costello Eithne, Goldring Christopher E, Copple Ian M, Park B Kevin, Palmer Daniel H, Kitteringham Neil R
Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Oncotarget. 2018 Jun 5;9(43):27104-27116. doi: 10.18632/oncotarget.25497.
Nrf2 is a transcription factor that regulates cellular stress response and irinotecan-metabolising pathways. Its aberrant activity has been reported in a number of cancers, although relatively few studies have explored a role for Nrf2 in colorectal cancer (CRC). This study assessed the expression of Nrf2 in patient CRC tissues and explored the effect of Nrf2 modulation alone, or in combination with irinotecan, in human (HCT116) and murine (CT26) cell lines and in an orthotopic syngeneic mouse model utilising bioluminescent imaging. Using a tissue microarray, Nrf2 was found to be overexpressed (p<0.01) in primary CRC and metastatic tissue relative to normal colon, with a positive correlation between Nrf2 expression in matched primary and metastatic samples. experiments in CRC cell lines revealed that Nrf2 siRNA and brusatol, which is known to inhibit Nrf2, decreased viability and sensitised cells to irinotecan toxicity. Furthermore, brusatol effectively abrogated CRC tumour growth in subcutaneously and orthotopically-allografted mice, resulting in an average 8-fold reduction in luminescence at the study end-point (p=0.02). Our results highlight Nrf2 as a promising drug target in the treatment of CRC.
Nrf2是一种转录因子，可调节细胞应激反应和伊立替康代谢途径。尽管相对较少的研究探讨了Nrf2在结直肠癌（CRC）中的作用，但已有报道称其在多种癌症中存在异常活性。本研究评估了Nrf2在患者CRC组织中的表达，并利用生物发光成像在人（HCT116）和小鼠（CT26）细胞系以及原位同基因小鼠模型中探讨了单独调节Nrf2或与伊立替康联合调节Nrf2的效果。使用组织微阵列发现，相对于正常结肠，原发性CRC和转移组织中Nrf2过表达（p<0.01），配对的原发性和转移样本中Nrf2表达呈正相关。在CRC细胞系中的实验表明，Nrf2 siRNA和已知可抑制Nrf2的bruceatol可降低细胞活力并使细胞对伊立替康毒性敏感。此外，bruceatol有效消除了皮下和原位异体移植小鼠中的CRC肿瘤生长，在研究终点时发光平均降低了8倍（p=0.02）。我们的结果突出了Nrf2作为CRC治疗中有前景的药物靶点。
