The relationship between NF-jB and resistance to radiation treatment in many tumor cell types has been generally well recognized. However, which members of the NF-jB family contribute to radiation resistance is unclear.In the present study, we demonstrate that RelB plays an important radioprotective role in aggressive prostate cancer cells, in part by the induction of antioxidant and antiapoptotic manganese superoxide dismutase (MnSOD) gene. RelB is both constitutively present and is inducible by radiation in aggressive prostate cancer cells. Using ectopically expressed dominant negative inhibitor, p100 mutant, and the siRNA approach, we demonstrate that selective inhibition of RelB significantly decreases the levels of MnSOD resulting in a significant increase in the sensitivity of prostate cancer cells to radiation treatment. These results demonstrate that RelB plays an important role in redox regulation of the cell and protects aggressive prostate cancer cells against radiation-induced cell death. Thus, inhibition of RelB could be a novel mechanism to radiosensitize prostate cancer.
Manganese superoxide dismutase (MnSOD) is a nuclear-encoded antioxidant enzyme that localizes to the mitochondria. Expression of MnSOD is essential for the survival of aerobic life. Transgenic mice expressing a luciferase reporter gene under the control of the human MnSOD promoter demonstrate that the level of MnSOD is reduced prior to the formation of cancer. Overexpression of MnSOD in transgenic mice reduces the incidences and multiplicity of papillomas in a DMBA/TPA skin carcinogenesis model. However, MnSOD deficiency does not lead to enhanced tumorigenicity of skin tissue similarly treated because MnSOD can modulate both the p53-mediated apoptosis and AP-1-mediated cell proliferation pathways. Apoptosis is associated with an increase in mitochondrial levels of p53 suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Activation of p53 is preventable by application of a SOD mimetic (MnTE-2-PyP 5+ ). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explain the observed mitochondrial dysfunction that leads to transcriptiondependent mechanisms of p53-induced apoptosis. Administration of MnTE-2-PyP 5+ following apoptosis but prior to proliferation leads to suppression of protein carbonyls and reduces the activity of AP-1 and the level of the proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Remarkably, the incidence and multiplicity of skin tumors are drastically reduced in mice that receive MnTE-2-PyP 5+ prior to cell proliferation. The results demonstrate the role of MnSOD beyond its essential role for survival and suggest a novel strategy for an antioxidant approach to cancer intervention.
Oxidative stress caused by reactive oxygen species is detoxified by intracellular antioxidant enzymes such as manganese superoxide dismutase (MnSOD), 2 catalase, and glutathione.Among these primary antioxidant enzymes, MnSOD is the enzyme that must function in order for all aerobic organisms to survive. MnSOD is a highly regulated SOD encoded by the sod2 located in human chromosome 6q25.3 (1, 2). The critical role of MnSOD as a cytoprotective enzyme is illustrated in both MnSOD knock-out and transgenic animal models. For instance, MnSOD knock-out mice develop cardiomyopathy and die within a few days after birth (3). MnSOD knock-out mice treated with a SOD mimetic were protected from systemic toxicity and from neonatal death (4). Conversely, transgenic mice overexpressing human MnSOD experienced less injury resulting from inflammation (5), cardio-toxic drugs (6), and pathological and physiological conditions leading to brain injury (7). The human MnSOD gene is a single-copy gene consisting of five exons interrupted by four introns with a typical splice junction (8). The sod2 from human, bovine, rat, and mouse share more than 90% homology in the coding sequence. The basal promoter of the sod2 has multiple transcription factor binding motifs containing Sp1 and Ap-2 binding sites. Functional studies in different cell lines with different levels of Sp1 and Ap-2 proteins suggest that cellular levels of these proteins differentially regulate the expression of the human MnSOD gene. Transcription factor Sp1 is essential and sufficient, whereas Ap-2 is unnecessary and antagonistic to the constitutive expression of the gene (9). Sp1 is a prototype member of a small family of transcription factors (Sp1, Sp2, Sp3, and Sp4) with homologous functional domains. Members of this family have an inhibitory domain in the N termini and four transcriptional activation domains (A, B, C, and D) (10). Transcriptional domains A and B are required for general and full activation, whereas domain C possesses very low activation (11), and domain D is required for synergistic activation (12). The Sp1 protein is capable of inducing homotypic, Sp1-Sp1 interaction (13) or forming heterotypic interactions with different classes of nuclear proteins such as TATA box-binding protein (TBP) (14), C/EBP (15), and YY1 (16). Because the MnSOD promoter does not contain a TATA or CAAT binding element, transcription of the MnSOD gene is dependent on Sp1-Sp1 interaction.The sod2 of mice and humans contains enhancer elements in the second intron of the gene (17,18
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