Flusberg DA, Roux J, Spencer SL, and Sorger PK (2013). Cells Surviving Fractional Killing by TRAIL Exhibit Transient but Sustainable Resistance and Inflammatory Phenotypes. Mol Biol Cell PMC3708725 PMID: 23699397.
Abstract
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 pre-existing, stochastic differences in the levels and activities of proteins regulating apoptosis. In this paper we examine the properties of cells that survive treatment with agonists of two distinct death receptors, TRAIL and anti-FasR antibodies. We find that “survivor” cells are highly resistant to a second ligand dose applied one day later. Resistance is reversible, resetting after several days of culture in the absence of TRAIL. “Reset” 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-kappaB-dependent inflammatory phenotype. Remarkably, reversible resistance is induced in the absence of cell death when caspase inhibitors are present and can be sustained for a week or more, also without cell death, by periodic ligand exposure. Thus, stochastic differences in cell state can have sustained consequences for sensitivity 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.