Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes (Molecular Biology of the Cell)
When clonal populations of human cells are exposed to apoptosis-inducing agents, some cells die and others survive. This fractional killing arises not from mutation but from preexisting, stochastic differences in the levels and activities of proteins regulating apoptosis. Here we examine the properties of cells that survive treatment with agonists of two distinct death receptors, tumor necrosis factor鈥搑elated apoptosis-inducing ligand (TRAIL) and anti-FasR antibodies. We find that 鈥渟urvivor鈥� cells are highly resistant to a second ligand dose applied 1 d later. Resistance is reversible, resetting after several days of culture in the absence of death ligand. 鈥淩eset鈥� cells appear identical to drug-naive cells with respect to death ligand sensitivity and gene expression profiles. TRAIL survivors are cross-resistant to activators of FasR and vice versa and exhibit an NF-魏B鈥揹ependent inflammatory phenotype. Remarkably, reversible resistance is induced in the absence of cell death when caspase inhibitors are present and can be sustained for 1 wk or more, also without cell death, by periodic ligand exposure. Thus stochastic differences in cell state can have sustained consequences for sen颅sitivity to prodeath ligands and acquisition of proinflammatory phenotypes. The important role played by periodicity in TRAIL exposure for induction of opposing apoptosis and survival mechanisms has implications for the design of optimal therapeutic agents and protocols.