Overexpression of mitochondrial manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin‐1, tumor necrosis factor, selected anticancer drugs, and ionizing radiation

Hirose, Kunitaka; Longo, Dan L.; Oppenheim, Joost J.; Matsushima, Kouji

doi:10.1096/fasebj.7.2.8440412

Cited by 316 publications

(170 citation statements)

References 32 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…10). Elevation of cellular radiation resistance by MnSOD has historically been observed as an enhancement of the initial slope or α component of the survival curve [4,[8][9][10]23]. To facilitate a more quantitative analysis of the protective effects of MnSOD, protection enhancement ratios (PER), defined by the ratio of the α components of the radiation survival curves describing the survival responses of control and WR1065 treated HMEC, i.e., α C /α WR1065 , were determined and are listed in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…When elevated in cells, it is known to confer among other things an enhanced resistance against the cytotoxic effects of ionizing radiation [4,[8][9][10]23,24]. The MnSOD gene contains multiple transcription factor-binding motifs that include sites for AP1, AP2, Sp1, CREB, and NFκB [19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

“…MnSOD is known to confer radiation resistance to cells when elevated over control levels [4,5,8,9,38]. Therefore, it is reasonable to expect that cells experiencing increased MnSOD levels will also exhibit an enhanced radiation-resistant phenotype corresponding to the kinetics and relative magnitude of MnSOD elevation following exposure to an inducing agent such as the nonprotein thiol WR1065.…”

Section: Discussionmentioning

confidence: 99%

“…The resulting survival curves were analyzed using an α/β model and compared using a Z test to determine levels of significant difference. Because MnSOD has been demonstrated to primarily affect the initial slope of the survival curve [4,9,23,24], an analysis and comparison of the α parameters of the survival curves were made. To facilitate a comparison between the various treatment conditions an α-protection enhancement ratio (αPER), defined as α control /α WR1065 , was used.…”

Section: Irradiation Conditions and Survival Assaymentioning

confidence: 99%

“…Mitochondria have been demonstrated to play an important role in the apoptotic processes induced by ionizing radiation, including the release of cytochrome c and the activation of caspase 3 that leads to PARP cleavage and subsequent DNA strand breaks [4,6,7]. Consistent with the role of mitochondrial damage leading to cell death, overexpression of MnSOD in cells induced by tranfection of an MnSOD transgene gives rise to an enhanced radioresistance and to an inhibition of radiation-induced apoptosis [8][9][10]. Furthermore, it has been demonstrated that localization of superoxide dismutase within the mitochondria is a requirement for subsequent radioprotection against cellular damage [4].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Murley

Kataoka

Weydert

et al. 2006

Free Radical Biology and Medicine

View full text Add to dashboard Cite

The free radical scavenger WR1065 (SH) is the active thiol form of the clinically approved cytoprotector amifostine. At doses of 40 μM and 4 mM it can activate the redox-sensitive nuclear transcription factor κB (NFκB) and elevate the expression of the antioxidant gene manganese superoxide dismutase (MnSOD) in human microvascular endothelial cells (HMEC). MnSOD contains binding motifs for a number of transcription factors other than NFκB and codes for a potent antioxidant enzyme localized in the mitochondria that is known to confer enhanced radiation resistance to cells. The purpose of this study was to determine the effect of WR1065 exposure on the various transcription factors known to affect MnSOD expression along with the subsequent kinetics of intracellular elevation of MnSOD protein levels and associated change in sensitivity to ionizing radiation in HMEC. Cells were grown to confluence and exposed to WR1065 for 30 min. Affects on the transcription factors AP1, AP2, CREB, NFκB, and Sp1 were monitored as a function of time ranging from 30 min to 4 h after drug exposure using a gel-shift assay. Only NFκB exhibited a marked activation and that occurred 30 min following the cessation of drug exposure. MnSOD protein levels, as determined by Western blot analysis, increased up to 16-fold over background control levels by 16 h following drug treatment, and remained at 10-fold or higher levels for an additional 32 h. MnSOD activity was evaluated using a gel-based assay and was found to be active throughout this time period. HMEC were irradiated with X-rays either in the presence of 40 μM or 4 mM WR1065 or 24 h after its removal when MnSOD levels were most elevated. No protection was observed for cells irradiated in the presence of 40 μM WR1065. In contrast, a 4 mM dose of WR1065 afforded an increase in cell survival by a factor of 2. A "delayed radioprotective" effect was, however, observed when cells were irradiated 24 h later, regardless of the concentration of WR1065 used. This effect is characterized as an increase in survival at the 2 Gy dose point, i.e., a 40% increase in survival, and an increase in the initial slope of the survival curve by a factor of 2. The anti-inflammatory sesquiterpene lactone, Helenalin, is an effective inhibitor of NFκB activation. HMEC were exposed to Helenalin for 2 h at a nontoxic concentration of 5 μM prior to exposure to WR1065. This treatment not only inhibited activation of NFκB by WR1065, but also inhibited the subsequent elevation of MnSOD and the delayed radioprotective effect. A persistent marked elevation of MnSOD in cells following their exposure to a thiol-containing reducing agent such as WR1065 can result in an elevated resistance to the cytotoxic effects of ionizing radiation and represents a novel radioprotection paradigm.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Irradiation Conditions and Survival Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Murley

Kataoka

Weydert

et al. 2006

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

Overexpression of manganese superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype

Oberley

et al. 1998

Prostate

133

View full text Add to dashboard Cite

Interleukin 1 (IL-1) production is not essential for acquired resistance of human A375 melanoma cells to anti-proliferative effect of IL-1

et al. 1996

View full text Add to dashboard Cite

The proliferation of human melanoma cell line A375-6 is inhibited by interleukin I (IL-I). However, the cells acquired resistance to IL-I after a long period of culture. We have reported that 2 resistant subclones, A375-R8 and -R19, produced IL-la constitutively and that IL-I induced IL-6 production in an autocrine manner. Therefore, we supposed that IL-la production renders the cells resistant to IL-I. To investigate the relationship between IL-la production and IL-I resistance, we transfected the IL-I a expression plasmid to the IL-I -sensitive clone, A375-6, and the anti-sense mRNA expression plasmid to IL-I-resistant cells, A375-R8 and -R19. A375-6MS, a transfectant of mature IL-la expression plasmid, expressed IL-la mRNA and produced IL-I activity at a level comparable to the resistant cells. The transfectant also produced IL-6 and exhibited augmented expression of Mn-SOD mRNA. However, IL-I sensitivity of this transfectant was not affected. With respect to sensitivity to anti-proliferative effects of other cytokines, such as IL-6 and TNFa, there was no difference between the transfectant and parent cells. Although A375-R8PH I 0 and -R19PH 10, transfectants of IL-la anti-sense mRNA expression plasmid, exhibited a decrease in the level of IL-l production, their IL-I sensitivity did not differ from parent cells. These results, therefore, suggest that IL-la production is not essential or suffkient for the acquisition of resistance to the antiproliferative effect of IL-I.o 1996 Wilq-Liss, Inc.IL-1 is a multifunctional cytokine that regulates immunoreaction, inflammation, hematopoiesis and homeostasis (Dinarello, 1994). IL-1 also regulates the proliferation of various cell types in both positive and negative manners. Thymocytes, B cells and fibroblasts are representatives that proliferate in response to I G 1 (Gery et al., 1972; Freedman et al., 1988;Schmidt et al., 1982). However, the proliferation of many cell types, including several human mammary tumor cell lines, the murine myeioid leukemic cell line (Ml) and human endothelial cells, is inhibited by IL-1 (Gaffney and Tsai, 1986;Onozaki et al., 1987; Maier et al., 1990).The human melanoma cell line A375-6 is the first found to be inhibited of its proliferation by IL-1 (Onozaki et al., 1985). We have noticed that A375-6 cells became resistant to IL-1 after a long period of culture. Two IL-1-resistant subclones, A375-RB and -R19, were obtained, and their characteristics have been studied. These 2 subclones expressed functional IL-1 receptor regardless of their resistance to IL-1 and produced IL-la constitutively. They also produced IL-6 constitutively, and the production was shown to result from the autocrine effect of endogenous IL-la. The cells also became resistant to the anti-proliferative effect of IL-6 (Araki et at., 1994).The progression of human melanoma has been extensively studied. In an early stage (the radial growth phase), the growth of melanoma cells depends on several growth factors and can be inhibited by several cytokines, such as transforming...

show abstract

Overexpression of mitochondrial manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin‐1, tumor necrosis factor, selected anticancer drugs, and ionizing radiation

Cited by 316 publications

References 32 publications

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

Overexpression of manganese superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype

Interleukin 1 (IL-1) production is not essential for acquired resistance of human A375 melanoma cells to anti-proliferative effect of IL-1

Contact Info

Product

Resources

About