Docosahexaenoic acid sensitizes Ramos cells to Gamma-irradiation-induced apoptosis through involvement of PPAR-gamma activation and NF-kappaB suppression.

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.