Overexpression of Par-4 Increases TRAIL-Induced Apoptosis in Neoplastic Lymphocytes by Diminishing Expression of Inhibitors-of-Apoptosis-Proteins and by Enforcing Activation of Initiator- and Executionercaspases.

Acknowledging the previously demonstrated deregulated expression of the prostate-apoptosis-response-gene-4 (par-4) in ex vivo cells of patients suffering from acute and chronic lymphatic leukemias, we hypothesized that expression of par-4 determines sensitivity of neoplastic lymphocytes towards TRAIL-induced apoptosis. Evaluating this hypothesis we thus demonstrate, that par-4-transfected Jurkat cells incubated with the agonistic TRAIL-antibody CH11 exhibit a considerably increased rate of apoptosis as compared to their par-4-negative counterparts. Outlining the underlying molecular mechanisms we provide evidence, that par-4 promotes activation of the initiator caspase-8. Despite upregulating Bcl-2, overexpression of par-4 enhances cleavage of Bid and activation of caspase-9, resulting in an enforced activation of the executioner caspases-6 and -7, whereas caspase-3 remains unaltered. These effects are observed with a concomittant down-regulation of the inhibitor-of-apoptosis proteins cIAP-1 and XIAP. In conclusion, we here provide first evidence that expression of par-4 augments sensitivity of neoplastic lymphocytes to TRAIL-induced cell death, and describe the impact of par-4-expression on key molecules considered crucial in the induction of apoptosis via the extrinsic pathway.