Zand Hamid, Rahimipour Ali, Salimi Saideh, Shafiee Sayed Mohammad
National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University M. C., Tehran, Iran.
Mol Cell Biochem. 2008 Oct;317(1-2):113-20. doi: 10.1007/s11010-008-9838-x. Epub 2008 Jun 20.
Gamma-irradiation (Gamma-IR) resistance is a character of many malignant cells that decreases the efficacy of radiotherapy. Although ionizing radiation activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of nuclear factor-kappa B appears to be a well-conserved response in tumor cells exposed to Gamma-IR which can lead to the inhibition of radiation-induced apoptosis. Thus, inhibition of NF-kappaB activation is an important strategy to abolish radioresistance. Recently, we have demonstrated that docosahexaenoic acid (DHA; 22:6 n-3 polyunsaturated fatty acids)-induced apoptosis may occur via ligand-dependent transcription factor, peroxisome proliferator-activated receptors-gamma. Moreover, many reports described that activation of PPAR-gamma can lead to the induction of apoptosis through NF-kappaB inhibition. Therefore, we addressed the mechanism that NF-kappaB is a downstream target of DHA and may be involved in the process of radiosensitization. Ramos cells are a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line. The results of present study showed that cotreatment of Ramos cells with low doses of DHA and Gamma-IR leads to marked phosphorylation of IkappaB and translocation of p65/NF-kappaB to nucleus in parallel with increase in apoptosis. Preincubation of the cells with GW9662, a selective antagonist for PPAR-gamma, significantly prevented NF-kappaB activation profile. Taken together, these results suggest that low concentration of DHA inhibited Gamma-IR-induced activation of NF-kappaB and sensitized Ramos cells to IR-induced cytotoxicity. Pretreatment of Ramos cells with GW9662 abrogated the ability of DHA to inhibit Gamma-IR-induced activation of NF-kappaB and diminished the DHA radiosensitizing effect indicating that PPAR-gamma may act as a mediator of DHA in inhibition of NF-kappaB. Taken together, these results suggest that low concentration of DHA inhibited Gamma-IR-induced activation of NF-kappaB and sensitized Ramos cells to IR-induced cytotoxicity. Pretreatment of Ramos cells with GW9662 abrogated the ability of DHA to inhibit Gamma-IR-induced activation of NF-kappaB and diminished the DHA radiosensitizing effect indicating that PPAR-gamma may act as a mediator of DHA in inhibition of NF-kappaB.
γ射线照射（Gamma-IR）抗性是许多恶性细胞的一种特性，它会降低放射治疗的疗效。尽管电离辐射会激活多种细胞因子，这些因子会因剂量和组织特异性而有所不同，但核因子-κB的激活似乎是暴露于Gamma-IR的肿瘤细胞中一种保守的反应，这可能导致辐射诱导的细胞凋亡受到抑制。因此，抑制NF-κB激活是消除放射抗性的重要策略。最近，我们已经证明二十二碳六烯酸（DHA；22:6 n-3多不饱和脂肪酸）诱导的细胞凋亡可能通过配体依赖性转录因子过氧化物酶体增殖物激活受体-γ发生。此外，许多报告描述PPAR-γ的激活可通过抑制NF-κB导致细胞凋亡的诱导。因此，我们研究了NF-κB是DHA的下游靶点且可能参与放射增敏过程的机制。Ramos细胞是一种高度抗辐射且p53缺陷的伯基特淋巴瘤细胞系。本研究结果表明，低剂量DHA与Gamma-IR联合处理Ramos细胞会导致IκB显著磷酸化以及p65/NF-κB易位至细胞核，同时细胞凋亡增加。用PPAR-γ的选择性拮抗剂GW9662对细胞进行预孵育可显著阻止NF-κB激活谱。综上所述，这些结果表明低浓度的DHA抑制Gamma-IR诱导的NF-κB激活，并使Ramos细胞对IR诱导的细胞毒性敏感。用GW9662对Ramos细胞进行预处理消除了DHA抑制Gamma-IR诱导的NF-κB激活的能力，并减弱了DHA的放射增敏作用，表明PPAR-γ可能作为DHA抑制NF-κB的介质。综上所述，这些结果表明低浓度的DHA抑制Gamma-IR诱导的NF-κB激活，并使Ramos细胞对IR诱导的细胞毒性敏感。用GW9662对Ramos细胞进行预处理消除了DHA抑制Gamma-IR诱导的NF-κB激活的能力，并减弱了DHA的放射增敏作用，表明PPAR-γ可能作为DHA抑制NF-κB的介质。
