These results indicated thatDMNBincreased the TRAIL induced apoptosis in K cells via enhancement of receptor mediated and caspase dependent apoptosis triggered by inhibition of DNA PK Akt pathway. Consequently, suppression of DNA PKcs Akt pathway might be a helpful tactic to boost the susceptibility to TRAILinduced cell death in TRAIL resistant human leukemic cells Discussion Induction of apoptosis in cancer cells by TRAIL may be a promising therapeutic principle in oncology, despite the fact that toxicity and resistance to TRAIL are limiting components. Without a doubt, many tumors remain resistant to TRAIL induced apoptosis, which associated to the dominance of anti apoptotic signals. Thus, we studied to recognize and target the anti apoptotic molecules regulating the TRAIL resistance in human leukemic K cells. From the current study, K R cells, a stable TRAIL sensitive variant isolated from K cells, showed down regulation of DNA PKcs Akt signaling pathway and a high sensitivity to TRAIL mediated growth inhibition and apoptosis as compared with K cells.
In addition, DNA PKcs deficient SCID cells showed also the down regulation of Akt phosphorylation and an elevated susceptibility to TRAIL induced cytotoxicity as in contrast with parental CB cells, suggesting the activity of DNA PKcs Akt NVP-LAQ824 signaling pathway may possibly influence the sensitivity of cells to TRAIL induced apoptosis. K R cells having a large sensitivity to TRAIL induced cytotoxicity showed profoundly reduced ranges of DNA PKcs and p Akt as compared with K cells. It’s been reported that the constitutively active Akt inhibits TRAIL induced apoptosis in various cancer cells such as prostate cancer, ovarian cancer, and acute leukemia cells , and that DNA PKcs acts upstream to Akt and directly phosphorylates and activates Akt . Thus, the reduced action of DNKA PK and Akt may well be accountable for the larger sensitivity of the K R cells to TRAIL as compared with K cells. It have already been recommended the induction of TRAIL receptors is one of the major approaches to potentiate the TRAIL induced apoptosis.
Just lately, it has been demonstrated that inhibition of PIK Akt by RNA interference sensitized resistant colon cancer cells to TRAILinduced cell death by means of the induction of TRAIL receptors and activation of supplier XL765 caspase and caspase . Then we anticipated that DR and DR may perhaps be enhanced in K R cells. Nonetheless, K R cells had an elevated level of DR along with a decreased level of DR as compared with K cells. Even though reduction of DR levels in K R cells could cancel the increased sensitivity to TRAIL obtained from an increased level of DR, this effect seemed to predominate over the cancelling impact from down regulation of DR, because the basal degree of DR was reduced than that of DR and TRAIL binds preferentially to DR .