Department of Molecular Microbiology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, 3109601, Haifa, Israel.
Department of Genetics and Developmental Biology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, 3109601, Haifa, Israel.
Cell Death Dis. 2019 Jun 11;10(6):455. doi: 10.1038/s41419-019-1680-4.
The adenovirus (Ad) E4orf4 protein contributes to efficient progression of virus infection. When expressed alone E4orf4 induces p53- and caspase-independent cell-death, which is more effective in cancer cells than in normal cells in tissue culture. Cancer selectivity of E4orf4-induced cell-death may result from interference with various regulatory pathways that cancer cells are more dependent on, including DNA damage signaling and proliferation control. E4orf4 signaling is conserved in several organisms, including yeast, Drosophila, and mammalian cells, indicating that E4orf4-induced cell-death can be investigated in these model organisms. The Drosophila genetic model system has contributed significantly to the study of cancer and to identification of novel cancer therapeutics. Here, we used the fly model to investigate the ability of E4orf4 to eliminate cancer tissues in a whole organism with minimal damage to normal tissues. We show that E4orf4 dramatically inhibited tumorigenesis and rescued survival of flies carrying a variety of tumors, including highly aggressive and metastatic tumors in the fly brain and eye discs. Moreover, E4orf4 rescued the morphology of adult eyes containing scrib cancer clones even when expressed at a much later stage than scrib elimination. The E4orf4 partner protein phosphatase 2A (PP2A) was required for inhibition of tumorigenesis by E4orf4 in the system described here, whereas another E4orf4 partner, Src kinase, provided only minimal contribution to this process. Our results suggest that E4orf4 is an effective anticancer agent and reveal a promising potential for E4orf4-based cancer treatments.
腺病毒 (Ad) E4orf4 蛋白有助于病毒感染的有效进展。单独表达时，E4orf4 会诱导 p53 和 caspase 非依赖性细胞死亡，在组织培养中，这种细胞死亡在癌细胞中比在正常细胞中更为有效。E4orf4 诱导的细胞死亡对癌细胞的选择性可能源于对各种调节途径的干扰，这些途径是癌细胞更依赖的，包括 DNA 损伤信号和增殖控制。E4orf4 信号在包括酵母、果蝇和哺乳动物细胞在内的几种生物体中是保守的，这表明可以在这些模型生物中研究 E4orf4 诱导的细胞死亡。果蝇遗传模型系统为癌症研究和新的癌症治疗方法的发现做出了重大贡献。在这里，我们使用果蝇模型来研究 E4orf4 在不损害正常组织的情况下在整个生物体中消除癌症组织的能力。我们表明，E4orf4 可显著抑制肿瘤发生，并挽救携带各种肿瘤的果蝇的存活率，包括在果蝇大脑和眼盘中的高度侵袭性和转移性肿瘤。此外，E4orf4 挽救了含有 scrib 癌症克隆的成年眼睛的形态，即使在 scrib 消除后表达的时间晚得多也是如此。在我们描述的系统中，E4orf4 抑制肿瘤发生所需的 E4orf4 伴侣蛋白磷酸酶 2A (PP2A)，而另一个 E4orf4 伴侣 Src 激酶仅对此过程提供最小的贡献。我们的结果表明 E4orf4 是一种有效的抗癌剂，并揭示了基于 E4orf4 的癌症治疗的有希望的潜力。
