XIAP is not required for human tumor cell survival in the absence of an exogenous death signal

We utilized siRNA to systematically knock down XIAP in ten human tumor cell lines and then monitored both XIAP protein levels and cell viability over time. To examine the role of XIAP in the intrinsic versus extrinsic cell death pathways, we compared the viability of XIAP depleted cells treated either with a variety of mechanistically distinct, intrinsic pathway inducing agents, or the canonical inducer of the extrinsic pathway, TNF-related apoptosis-inducing ligand (TRAIL).XIAP knockdown had no effect on the viability of six cell lines, whereas the effect in the other four was modest and transient. XIAP knockdown only sensitized tumor cells to TRAIL and not the mitochondrial pathway inducing agents.These data indicate that XIAP has a more central role in regulating death receptor mediated apoptosis than it does the intrinsic pathway mediated cell death.An underlying feature of all human cancer is uncontrolled cell proliferation. However, for a tumor to increase in cell mass and malignant potential, the increase in replication rate must be accompanied by suppression of apoptosis [1]. While tumor cells can subvert many apoptotic regulators, the anti-apoptotic IAP family is thought to have a central role in this process.There are eight IAPs in humans. All IAPs contain multiple functional domains that potentially modulate many biological processes, including apoptosis. For instance, IAPs have a role in cell-cycle regulation through mitotic spindle formation, ubiquitination of target proteins, and modulation of several signal transduction pathways [2]. Elevated IAP protein levels are common in many tumor types, and a wealth of data supports their role in suppressing cell death, although the exact mechanisms by which different IAPs mediate this effect remains unclear [3,4]XIAP is the most thoroughly characterized of this family, and is the only member that can directly inhibit the proteolytic activity of caspases in vitro (reviewed in Eckelmen [5]). Caspase inhibition is