SMAC dependency of XIAP mediated chemoresistance

An important hallmark of tumor cells is their resistance to apoptosis. Apoptosis is a tightly regulated cellular response that ultimately results in the elimination and disposal of unwanted or damaged cells. Apoptosis is brought about by a family of proteases known as the caspases, the activity of which is responsible for the organized destruction of the cell. Each step of the apoptotic signaling cascade is under stringent control. Apoptotic signaling can be regulated at the apical point of the apoptotic cascade by controlling the translation of death-inducing signals into proteolytic activity or more critically by direct modulation of proteolytic activity of caspases. The later is modulated by direct interaction of caspases with members of the inhibitor of apoptosis protein (IAP) family, the most studied one, X-linked IAP (XIAP), has evolved to potently inhibit the enzymatic activity of mammalian caspases. By efficiently inhibiting caspases XIAP has been shown to block apoptosis and described as a factor conferring resistance against different chemotherapeutic drugs (chemoresistant factor) in a variety of tumor cells. Furthermore, elevated XIAP expression has been frequently observed in several tumor tissues and XIAP targeting sensitizes diverse tumor cell lines for chemotherapeutic agents underlining the role of XIAP in tumor chemoresistance. However, by generating stable cell lines overexpressing XIAP the data provided show that XIAP overexpression alone does not generate a chemoresistant phenotype. Experiments evaluating both XIAP overexpression and stable knock-down of SMAC, a critical regulator of XIAP, show that XIAP action as a chemoresistant factor is tightly controlled by SMAC. In contrast to Bcl2 that acts as a mitochondrial gatekeeper, XIAP does not alter mitochondrial functions. Cytostatic drugs readily induce release of SMAC in cells with functionally intact mitochondria independent of caspase action, thereby completely neutralizing the anti-apoptotic action of even overexpressed XIAP. Although increased cytotoxic activity by different cytostatic drugs was observed, XIAP targeting failed to restore chemosensitivity in chemoresistant Hodgkin Lymphoma-derived cell lines indicating limited involvement of XIAP in chemoresistance. Unlike chemotherapeutic agents, XIAP targeting resulted in complete reactivation of the apoptotic machinery in response to grzB treatment regardless of mitochondrial functional state. These data demonstrated for the first time that it is essential to assess the mitochondrial capacity to release SMAC as well as the expression levels of both XIAP and SMAC in order to predict the chemosensitivity of particular tumours, a relationship that has not previously been recognised

Nonstandard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants