The proteasome inhibition enhances apoptosis by P53 expression and the dissipation of mitochondrial transmembrane potential in TRAIL-resistant lung cancer cells
2009
Seol, J.W., Chonbuk National University, Jeonju, Republic of Korea | Park, S.Y., Chonbuk National University, Jeonju, Republic of Korea
The ubiquitin-proteasome mediated protein degradation pathway plays an important role in regulating both cell proliferation and cell death. Proteasome inhibitors are well known to induce apoptosis in various human cancer cell lines. We investigated the effect of combined treatment with proteasome inhibitor and TRAIL, and a possible mechanism of the enhancing apoptosis by the both treatment, on TRAIL-resistant non-small cell lung cancer. A549 cells were exposed to the N-Acetyl-Leu-Leu-Norleu-al(ALLN) as a proteasome inhibitor and then treated with recombinant TRAIL protein. In A 549 cells under proteasome inhibition conditions by pretreatment with ALLN, TRAIL treatment significantly decreased cell vibility compared to that ALLN and TRAIL alone treatment. Also, the both treatment induced cell damage through DNA fragmentation and p53 expression. In addition, the combined treatment of both markedly increased caspase-8 activation, especially the exposure for 2h, and Bax expression and induced the dissipation of mitochondrial transmembrane potential in A549 cells. Taken together, these findings showed that proteasome inhibition by ALLN enhanced TRAIL-induced apoptosis via DNA degradation by activated P53 and mitochondrial transmembrane potential loss by caspase-8 activation and bax expression. Therefore, our results suggest that proteasome inhibitor may be used a very effectively chemotherapeutic agent for the tumor treatment, especeally TRAIL-resistant tumor cell.
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