Selective elimination of cancer cells by the adenovirus E4orf4 protein in a Drosophila cancer model: a new paradigm for cancer therapy

Helit Rosen,Tamar Kleinberger,Adi Salzberg,Rakefet Sharf,Antonina Pechkovsky

doi:10.1038/s41419-019-1680-4

Helit Rosen, Tamar Kleinberger + Show 3 more

Open Access

https://doi.org/10.1038/s41419-019-1680-4

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Abstract

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.

Highlights

1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction The adenovirus E4orf[4] protein is a multifunctional viral regulator, which contributes to regulation of the progression of viral infection[1,2] and to inhibition of the cellular DNA damage response (DDR), increasing the efficiency of adenovirus replication[3,4]
We previously reported that two E4orf[4] partners, phosphatase 2A (PP2A) and Src, contributed in an additive manner to the mild
Induced cell-death was more efficient in mammalian cancer cells than in normal cells[13]

Summary

Introduction

E4orf[4] protein is a multifunctional viral regulator, which contributes to regulation of the progression of viral infection[1,2] and to inhibition of the cellular DNA damage response (DDR), increasing the efficiency of adenovirus replication[3,4]. Our studies in normal Drosophila tissues demonstrated that E4orf[4] induced both caspase-dependent and –independent cell-death in the fly, and inhibited classical apoptosis, thereby causing minimal tissue damage and a marginal effect on fly survival[12]. Studies in mammalian cells revealed that E4orf4-induced cell-death was more efficient in oncogene-transformed cells than in normal cells[13], indicating that investigation of. Several E4orf[4] cellular partners that contribute to E4orf4-induced cell-death have been described, including protein phosphatase 2A (PP2A) and Src kinases[2]. E4orf[4] binds the heterotrimeric PP2A holoenzyme through direct association with its regulatory B55 subunit[14,15]

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