Lee Jung Tae, Lee Tae-Jin, Park Jong-Wook, Kwon Taeg Kyu
Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, Jung-Gu, Taegu 700-712, Korea.
Int J Oncol. 2009 May;34(5):1455-60.
Recent studies establish a critical role of selenium in cancer prevention in vitro and in vivo. Selenium may sensitize TRAIL-mediated apoptosis in human renal cancer cells and increase therapeutic efficacy. In this study, we demonstrate that concomitant administration of TRAIL and Se-methylselenocysteine (Se-MSC) produces synergistic effects on the induction of apoptosis in Caki cells. Se-MSC rapidly and specifically down-regulates expression of the Bcl-2 at transcriptional level. The forced expression of Bcl-2 attenuated Se-MSC plus TRAIL-mediated apoptosis, suggesting that the lessened Bcl-2 expression caused by Se-MSC treatment is critical to the increased sensitivity to TRAIL in renal cancer cells. In addition, we demonstrate that the synergistic effects of Se-MSC and TRAIL result from the activation of the caspase-dependent pathways. Co-administration of HA14-1, a small molecule Bcl-2 inhibitor and TRAIL increased apoptosis in Caki cells. Taken together, Se-MSC-mediated down-regulation of Bcl-2 is able to sensitize Caki cells for TRAIL-induced apoptosis. Thus, selenium-based dietary compounds may help to overcome resistance to TRAIL-mediated apoptosis in renal cancer cells.
近期研究证实了硒在体外和体内癌症预防中的关键作用。硒可能会使人类肾癌细胞对TRAIL介导的凋亡敏感化，并提高治疗效果。在本研究中，我们证明同时给予TRAIL和硒代甲基硒代半胱氨酸（Se-MSC）对Caki细胞凋亡的诱导产生协同作用。Se-MSC在转录水平迅速且特异性地下调Bcl-2的表达。Bcl-2的强制表达减弱了Se-MSC加TRAIL介导的凋亡，这表明Se-MSC处理导致的Bcl-2表达降低对于肾癌细胞对TRAIL敏感性的增加至关重要。此外，我们证明Se-MSC和TRAIL的协同作用源于半胱天冬酶依赖性途径的激活。小分子Bcl-2抑制剂HA14-1与TRAIL共同给药可增加Caki细胞的凋亡。综上所述，Se-MSC介导的Bcl-2下调能够使Caki细胞对TRAIL诱导的凋亡敏感化。因此，基于硒的膳食化合物可能有助于克服肾癌细胞对TRAIL介导凋亡的抗性。
