Center for Healthcare Technology Development ,Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Korea.
Exp Mol Med. 2011 Mar 31;43(3):138-45. doi: 10.3858/emm.2011.43.3.016.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is one of the most promising candidates for cancer therapeutics. However, many osteosarcomas are resistant to TRAIL. Bisphosphonates are very effective in the treatment of bone problems associated with malignancies; the antitumor effects are due to the inhibition of protein prenylation that is essential for cell function and survival. The purpose of this study was to determine the effects of bisphosphonates on TRAIL-resistant MG 63 human osteosarcoma cells. The cells showed no response to TRAIL alone; however, pre-treatment with bisphosphonates significantly increased TRAIL-mediated apoptosis and cellular activation of caspase-3. Bisphosphonates significantly induced mRNA and protein expression of the TRAIL receptor, DR5. Bisphosphonates induced protein unprenylation in MG 63 cells; in addition, co-treatment with TRAIL also significantly increased protein unprenylation. Blocking of protein unprenylation using geranylgeraniol attenuated the cellular responses, including cell apoptosis and protein unprenylation induced by bisphosphonates and TRAIL. This is the first study to demonstrate that bisphosphonates markedly enhanced TRAIL-induced apoptosis in human osteosarcoma cells. These findings suggest that bisphosphonates may be a new and effective anticancer treatment with TRAIL proteins for TRAIL-resistant cancer cells.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是 TNF 细胞因子超家族的成员之一，是癌症治疗最有前途的候选药物之一。然而，许多骨肉瘤对 TRAIL 具有抗性。双膦酸盐在治疗与恶性肿瘤相关的骨骼问题方面非常有效；其抗肿瘤作用是由于抑制了对细胞功能和存活至关重要的蛋白质异戊烯化。本研究旨在确定双膦酸盐对 TRAIL 耐药的 MG63 人骨肉瘤细胞的影响。这些细胞单独用 TRAIL 处理时没有反应；然而，用双膦酸盐预处理可显著增加 TRAIL 介导的细胞凋亡和 caspase-3 的细胞激活。双膦酸盐可显著诱导 TRAIL 受体 DR5 的 mRNA 和蛋白表达。双膦酸盐诱导 MG63 细胞中的蛋白质去异戊烯化；此外，用 TRAIL 共同处理也显著增加了蛋白质去异戊烯化。使用香叶基香叶醇阻断蛋白质去异戊烯化可减弱细胞反应，包括双膦酸盐和 TRAIL 诱导的细胞凋亡和蛋白质去异戊烯化。这是第一项表明双膦酸盐可显著增强人骨肉瘤细胞中 TRAIL 诱导的细胞凋亡的研究。这些发现表明，双膦酸盐可能是一种新的有效的抗癌治疗方法，与 TRAIL 蛋白联合用于 TRAIL 耐药的癌细胞。
