Therapeutic molecular targeting of 15-lipoxygenase-1 in colon cancer.
Therapeutic molecular targeting of 15-lipoxygenase-1 in colon cancer.
复制标题
结肠癌中 15-脂氧合酶-1 的治疗性分子靶向。
DOI：
10.1038/mt.2008.44
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发表时间：
2008
期刊：
影响因子：
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通讯作者：
Shureiqi,Imad
中科院分区：
文献类型：
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作者：
Wu,Yuanqing;Fang,Bingliang;Yang,XiulanQ;Wang,Li;Chen,Dongning;Krasnykh,Victor;Carter,BingZ;Morris,JeffreyS;Shureiqi,Imad
为了更好地治疗癌症，正在开发细胞凋亡诱导的分子靶向。15-脂氧合酶-1（15-LOX-1）的下调与结直肠肿瘤发生有关。通过药剂在癌细胞中重新表达15-LOX-1诱导细胞凋亡。抗肿瘤剂也可以通过其他分子靶点诱导细胞凋亡。恢复癌细胞中15-LOX-1的表达是否足以在治疗上抑制结肠肿瘤的发生仍然是未知的。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纤维修饰增强了各种结肠直肠癌细胞系中的15-LOX-1基因转导，（ii）腺病毒载体递送使结肠癌细胞系中的15-LOX-1表达和酶活性恢复到治疗水平，和（iii）15-LOX-1表达下调抗凋亡蛋白X-连锁凋亡抑制蛋白（XIAP）和BcL-XL的表达，激活半胱天冬酶-3，因此，选择性分子靶向15-LOX-1表达足以重建结肠癌细胞的凋亡并抑制肿瘤发生。这些数据提供了进一步发展的治疗策略，以靶向15-LOX-1分子治疗结肠肿瘤发生的基本原理。
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 inin vitroandin vivomodels 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 survivalin vitroand the growth of colon cancer xenograftsin 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.