Center for Healthcare Technology Development, Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
Mol Med Rep. 2011 Nov-Dec;4(6):1255-9. doi: 10.3892/mmr.2011.558. Epub 2011 Aug 16.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane cytokine and a potent inducer of apoptosis in cancer cells. However, some cancer cells, particularly prostate cancer cells, such as LNCaP cells, were found to be resistant to TRAIL. In the present study, we demonstrate that the proteasome inhibitor ALLN significantly enhanced TRAIL-induced apoptosis by up-regulating TRAIL/Apo2L death receptor 5 expression in LNCaP cells. LNCaP cells were exposed to ALLN for 3 h and treated with recombinant TRAIL protein. ALLN alone induced a 20% cell death after a 3‑h treatment; however, pretreatment with ALLN induced death to more than 80% of cells after 3 h of TRAIL treatment. ALLN also enhanced the cell death of TRAIL-sensitive/resistant prostate cancer and other cancer cell lines. Western blotting results showed that the combination of ALLN and TRAIL increased the levels of activated caspase-8, -3 and DR-5 in LNCaP cells. Furthermore, we observed an increase in DR-5 expression following 3 h of treatment of ALLN alone. Taken together, our findings indicate that ALLN enhances TRAIL-induced apoptosis in LNCaP cells by up-regulating DR-5 expression. Thus, our results suggest that the combination of ALLN and TRAIL is a novel therapeutic strategy in TRAIL-resistant tumors.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是一种 II 型跨膜细胞因子，是癌细胞凋亡的有效诱导剂。然而，一些癌细胞，特别是前列腺癌细胞，如 LNCaP 细胞，被发现对 TRAIL 具有抗性。在本研究中，我们证明蛋白酶体抑制剂 ALLN 通过上调 LNCaP 细胞中 TRAIL/Apo2L 死亡受体 5 的表达，显著增强了 TRAIL 诱导的细胞凋亡。将 LNCaP 细胞暴露于 ALLN 中 3 小时，并用重组 TRAIL 蛋白处理。ALLN 单独处理 3 小时后诱导 20%的细胞死亡；然而，ALLN 预处理后，在用 TRAIL 处理 3 小时后诱导的细胞死亡超过 80%。ALLN 还增强了 TRAIL 敏感/抗性前列腺癌和其他癌细胞系的细胞死亡。Western blot 结果显示，ALLN 和 TRAIL 的组合增加了 LNCaP 细胞中激活的 caspase-8、-3 和 DR-5 的水平。此外，我们观察到在用 ALLN 单独处理 3 小时后，DR-5 的表达增加。总之，我们的研究结果表明，ALLN 通过上调 DR-5 的表达增强了 LNCaP 细胞中 TRAIL 诱导的细胞凋亡。因此，我们的结果表明，ALLN 和 TRAIL 的组合是 TRAIL 抗性肿瘤的一种新的治疗策略。
