Butz Karin, Ristriani Tutik, Hengstermann Arnd, Denk Claudia, Scheffner Martin, Hoppe-Seyler Felix
Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg D-69120, Germany.
Oncogene. 2003 Sep 4;22(38):5938-45. doi: 10.1038/sj.onc.1206894.
The targeted inhibition of antiapoptotic factors in tumour cells may provide a rational approach towards the development of novel anticancer therapies. Using human papillomavirus (HPV)-transformed cells as a model system, we investigated if RNA interference (RNAi)-mediated gene silencing can be employed in order to overcome the apoptosis resistance of cancer cells. We found that both vector-borne and synthetic small interfering (si)RNAs, specifically directed against the antiapoptotic HPV E6 oncogene, restored dormant tumour suppressor pathways in HPV-positive cancer cells that are otherwise inactive in the presence of E6. This ultimately resulted in massive apoptotic cell death, selectively in HPV-positive tumour cells. These findings show that RNAi provides a powerful molecular strategy to inactivate intracellular E6 function efficiently. Moreover, they define E6 as a most promising therapeutic target to eliminate HPV-positive tumour cells specifically by RNAi. Thus, by sequence-specific targeting of antiapoptotic genes, siRNAs may be developed into novel therapeutics that can efficiently correct the apoptosis deficiency of cancer cells.
靶向抑制肿瘤细胞中的抗凋亡因子可能为开发新型抗癌疗法提供合理途径。我们以人乳头瘤病毒（HPV）转化细胞作为模型系统，研究了RNA干扰（RNAi）介导的基因沉默是否可用于克服癌细胞的凋亡抗性。我们发现，无论是载体介导的还是合成的小干扰（si）RNA，特异性针对抗凋亡的HPV E6癌基因，均可恢复HPV阳性癌细胞中原本在E6存在时无活性的休眠肿瘤抑制途径。这最终导致大量凋亡性细胞死亡，且选择性地发生在HPV阳性肿瘤细胞中。这些发现表明，RNAi提供了一种强大的分子策略，可有效使细胞内E6功能失活。此外，这些发现将E6定义为通过RNAi特异性消除HPV阳性肿瘤细胞的最有前景的治疗靶点。因此，通过对抗凋亡基因进行序列特异性靶向，siRNA可能会被开发成新型疗法，从而有效纠正癌细胞的凋亡缺陷。
