[Alternative cell death pathways: lessons learned from a viral protein]

Evidence indicates that a limited set of common genetic alterations is responsible for tumor progression and cancer cell resistance to current therapies. The ability of tumor cells to escape apoptosis induction, which normally occurs in response to deregulated oncogenic signaling, is a critical one. Recent work supports the existence of alternative physiological death programs, which seem effective in cancer cells bearing multiple defects in apoptotic regulators. The goal of this review is to highlight the importance of these alternative death programs and to present the adenovirus E4orf4 protein (Early region 4 open reading frame 4), as a unique molecular tool to identify key regulators of these pathways in cancer cells. Evidence indicates that E4orf4 hijacks the oncogenic functions of Src tyrosine kinases to activate a cell death program in cancer cells, which does not rely on the classical caspase pathways and bypasses Bcl-2. Recent findings support a critical role for endosomes-associated actin dynamics downstream of E4orf4-Src signaling, in the regulation of this cell death pathway.