Wu Yuanqing, Fang Bingliang, Yang Xiulan Q, Wang Li, Chen Dongning, Krasnykh Victor, Carter Bing Z, Morris Jeffrey S, Shureiqi Imad
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Mol Ther. 2008 May;16(5):886-892. doi: 10.1038/mt.2008.44. Epub 2016 Dec 8.
Molecular targeting for apoptosis induction is being developed for better treatment of cancer. Downregulation of 15-lipoxygenase-1 (15-LOX-1) is linked to colorectal tumorigenesis. Re-expression of 15-LOX-1 in cancer cells by pharmaceutical agents induces apoptosis. Antitumorigenic agents can also induce apoptosis via other molecular targets. Whether restoring 15-LOX-1 expression in cancer cells is therapeutically sufficient to inhibit colonic tumorigenesis remains unknown. We tested this question using an adenoviral delivery system to express 15-LOX-1 in in vitro and in vivo models of colon cancer. We found that (i) the adenoviral vector 5/3 fiber modification enhanced 15-LOX-1 gene transduction in various colorectal cancer cell lines, (ii) the adenoviral vector delivery restored 15-LOX-1 expression and enzymatic activity to therapeutic levels in colon cancer cell lines, and (iii) 15-LOX-1 expression downregulated the expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and BcL-XL, activated caspase-3, triggered apoptosis, and inhibited cancer cell survival in vitro and the growth of colon cancer xenografts in vivo. Thus, selective molecular targeting of 15-LOX-1 expression is sufficient to re-establish apoptosis in colon cancer cells and inhibit tumorigenesis. These data provide the rationale for further development of therapeutic strategies to target 15-LOX-1 molecularly for treating colonic tumorigenesis.
为了更好地治疗癌症，正在研发针对凋亡诱导的分子靶向治疗方法。15-脂氧合酶-1（15-LOX-1）的下调与结直肠癌的发生有关。通过药物制剂使癌细胞重新表达15-LOX-1可诱导凋亡。抗肿瘤药物也可通过其他分子靶点诱导凋亡。在癌细胞中恢复15-LOX-1表达是否足以在治疗上抑制结肠肿瘤发生尚不清楚。我们使用腺病毒递送系统在结肠癌的体外和体内模型中表达15-LOX-1来测试这个问题。我们发现：（i）腺病毒载体5/3纤维修饰增强了15-LOX-1基因在各种结直肠癌细胞系中的转导；（ii）腺病毒载体递送使15-LOX-1表达和酶活性在结肠癌细胞系中恢复到治疗水平；（iii）15-LOX-1表达下调了抗凋亡蛋白X连锁凋亡抑制蛋白（XIAP）和Bcl-XL的表达，激活了caspase-3，触发了凋亡，并在体外抑制了癌细胞存活，在体内抑制了结肠癌异种移植物的生长。因此，选择性分子靶向15-LOX-1表达足以在结肠癌细胞中重新建立凋亡并抑制肿瘤发生。这些数据为进一步开发针对15-LOX-1进行分子靶向治疗结肠肿瘤发生的治疗策略提供了理论依据。
