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Vol. 16, Issue 3, 1189-1199, March 2005

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Selective Inactivation of a Fas-associated Death Domain Protein (FADD)-dependent Apoptosis and Autophagy Pathway in Immortal Epithelial Cells

Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Submitted October 18, 2004; Accepted December 16, 2004
Monitoring Editor: Gerard Evan

Although evasion of apoptosis is thought to be required for the development of cancer, it is unclear which cell death pathways are evaded. We previously identified a novel epithelial cell death pathway that works in normal cells but is inactivated in tumor cells, implying that it may be targeted during tumor development. The pathway can be activated by the Fas-associated death domain (FADD) of the adaptor protein but is distinct from the known mechanism of FADD-induced apoptosis through caspase-8. Here, we show that a physiological signal (tumor necrosis factor-related apoptosis-inducing ligand) can kill normal epithelial cells through the endogenous FADD protein by using the novel FADD death domain pathway, which activates both apoptosis and autophagy. We also show that selective resistance to this pathway occurs when primary epithelial cells are immortalized and that this occurs through a mechanism that is independent of known events (telomerase activity, and loss of function of p53, Rb, INK4a, and ARF) that are associated with immortalization. These data identify a novel cell death pathway that combines apoptosis and autophagy and that is selectively inactivated at the earliest stages of epithelial cancer development.

Abbreviations used: DD, death domain; FADD, Fas associated death domain protein; TRAIL, tumor necrosis factor-related apoptosis inducing ligand.

^* Present address: Department of Pharmacology, University of Colorado Health Sciences Center, University of Colorado Health Sciences Center at Fitzsimons, P.O. Box 6511, Mail Stop 8303, Aurora, CO 80045-0511.

Address correspondence to: Andrew Thorburn (Andrew.Thorburn{at}uchsc.edu).

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