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 FADDinduced apoptosis through caspase-8. Here, we show that a physiological signal (tumor necrosis factor-related apoptosisinducing 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.
INTRODUCTIONBecause apoptosis can suppress tumor development, it is sometimes thought that cancer cells are generally resistant to apoptosis, whereas normal cells are sensitive. In fact, cancer cells are closer to their apoptotic threshold than their normal counterparts and often die more easily than normal cells in response to apoptotic stimuli (Evan and Vousden, 2001;Lowe et al., 2004). Apoptosis sensitization in cancer cells occurs because growth-promoting oncogenic events such as Myc expression (Evan and Littlewood, 1998;Evan and Vousden, 2001;Pelengaris et al., 2002), Rb inactivation (Chau and Wang, 2003), E2F activation (Nahle et al., 2002), and cyclin D3 expression (Mendelsohn et al., 2002) raise the levels of apoptotic proteins or make it easier to activate these molecules and thus reduce the threshold at which apoptosis is activated. Activated oncogenes can also sensitize cells to apoptosis by promoting loss of inhibitors of apoptosis that exist in primary cells (Duelli and Lazebnik, 2000). Immortalization and transformation also sensitize cells to nonapoptotic death (Fehrenbacher et al., 2004).If cancer cells die more easily than their normal counterparts, which cell death pathways are evaded during tumor development? One answer is that cancer cells must remain below the lowered apoptotic threshold for undergoing stress-induced apoptosis that is caused by the oncogenes that drive cell growth. Indeed, it has been suggested that this may be sufficient to cause cancer without any other cellular defects (Green and Evan, 2002). However, this model does not exclude the possibility that there may also be specific cell death pathways that inhibit cancer development in normal cells that are specifically inactivated during tumor development. Such a pathway would be expected to have the unusual cha...
