The tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-KB (NF-KB) has been implicated, but its exact role is controversial. We studied different cell lines displaying varying responses to TRAIL and found that TRAIL can activate NF-KB in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-KB via adenoviral expression of the IKB-A super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-KB, pointing to a possible role of preactivated NF-KB in protection from TRAIL. Furthermore, we could reduce X-linked inhibitor of apoptosis protein (XIAP) levels in Panc-1 cells by inhibition of constitutively activated NF-KB and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-KB activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-KB and/or XIAP only in tumor cells with constitutively

SummaryWe have analysed 11 human-specific Alu insertion polymorphisms in the Balkans to elucidate the origins of the Aromuns, a linguistic isolate inhabiting scattered areas in the Balkan Peninsula. Four Aromun samples (two from the Republic of Macedonia, one from Albania, and one from Romania) and five neighbouring populations (Macedonians, Albanians, Romanians, Greeks, and Turks) were analysed by means of genetic distances, principal components and analyses of the molecular variance (AMOVA). Three hypotheses were tested: Aromuns are Romanophonic Greeks; the result of a Romanian southward migration; or local descendants of the Thracians. The analyses show that the Aromuns do not constitute a homogeneous group separated from the rest of the Balkan populations. Grouping by language or geography does not explain the genetic differences observed in the region, suggesting a lack of genetic structure in the area. Aromuns do not seem to be particularly related to Greeks, Romanians, or to other Romance speakers. The Aromuns might have their origin to the south of the Danube river, with extensive gene flow with the neighbouring populations. The present results suggest a common ancestry of all Balkan populations, including Aromuns, with a lack of correlation between genetic differentiation and language or ethnicity, stressing that no major migration barriers have existed in the making of the complex Balkan human puzzle.