Therapeutic potential of proapoptotic molecule Noxa in the selective elimination of tumor cells
Therapeutic potential of proapoptotic molecule Noxa in the selective elimination of tumor cells
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DOI：
10.1111/j.1349-7006.2009.01096.x
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发表时间：
2009-04
期刊：
影响因子：
5.7
通讯作者：
Saori Suzuki;M. Nakasato;T. Shibue;I. Koshima;T. Taniguchi
中科院分区：
文献类型：
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作者：
Saori Suzuki;M. Nakasato;T. Shibue;I. Koshima;T. Taniguchi
通过诱导细胞凋亡选择性地清除肿瘤细胞是肿瘤治疗中最重要的问题之一。在这种情况下，p53肿瘤抑制基因的人工表达一直是一种有吸引力的方法，许多研究表明其与其他疗法（如放疗或化疗）联合使用的疗效。如何在不影响正常细胞的情况下诱导癌细胞凋亡是目前肿瘤基因治疗的关键问题之一。在本研究中，我们研究了Noxa的潜力，Noxa是一种具有促凋亡活性的仅BH 3蛋白，在p53介导的凋亡途径下游发挥作用，选择性诱导肿瘤细胞凋亡。我们发现，在感染的重组腺病毒设计表达Noxa基因，诱导细胞凋亡在体外的几个人乳腺癌细胞系，但不是在正常的乳腺上皮细胞系。此外，瘤内注射表达Noxa的腺病毒导致源自乳腺癌细胞的移植肿瘤显著收缩，而对周围正常组织没有任何显著的不良影响。相比之下，Puma（另一种仅BH 3蛋白，也在p53通路下游发挥作用）的表达诱导了癌症和正常细胞的凋亡。因此，我们的研究结果表明，Noxa，而不是彪马，选择性地诱导人类肿瘤细胞凋亡的机制。这些数据为通过Noxa介导的选择性消除恶性细胞的癌症治疗提供了新的前景。（Cancer Sci 2009; 100：759-769）
The selective elimination of tumor cells by inducing apoptosis is one of the most important issues in cancer therapy. In this context, artificial expression of the p53 tumor‐suppressor gene has been an attractive approach and numerous studies have shown its efficacy in combination with other therapies such as radiation or chemotherapy. One of the critical issues for current cancer gene therapy is how to induce apoptosis in cancer cells without affecting normal cells. In the present study, we examined the potential of Noxa, a BH3‐only protein with proapoptotic activity that functions downstream of the p53‐mediated apoptotic pathway, to selectively induce apoptosis in tumor cells. We found that upon infection of a recombinant adenovirus contrived to express the Noxa gene, apoptosis was induced in vitro in several human breast cancer cell lines, but not in normal mammary epithelial cell lines. Furthermore, intratumoral injection of the Noxa‐expressing adenovirus resulted in marked shrinkage of the transplanted tumor derived from breast cancer cells without any notable adverse effect on the surrounding normal tissue. In contrast, the expression of Puma, another BH3‐only protein that also functions downstream of the p53 pathway, induced apoptosis in both cancer and normal cells. Thus, our results suggest a mechanism wherein Noxa, but not Puma, selectively induces apoptosis in human tumor cells. These data provide a new prospect for cancer therapy by the Noxa‐mediated selective elimination of malignant cells. (Cancer Sci 2009; 100: 759–769)