Korea Institute of Radiation and Medical science

Seoul, South Korea

Korea Institute of Radiation and Medical science

Seoul, South Korea
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Sahgal A.,University of Toronto | Ma L.,University of California at San Francisco | Weinberg V.,University of California at San Francisco | Gibbs I.C.,Stanford University | And 13 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: We reviewed the treatment for patients with spine metastases who initially received conventional external beam radiation (EBRT) and were reirradiated with 1-5 fractions of stereotactic body radiotherapy (SBRT) who did or did not subsequently develop radiation myelopathy (RM). Methods and Materials: Spinal cord dose-volume histograms (DVHs) for 5 RM patients (5 spinal segments) and 14 no-RM patients (16 spine segments) were based on thecal sac contours at retreatment. Dose to a point within the thecal sac that receives the maximum dose (P max), and doses to 0.1-, 1.0-, and 2.0-cc volumes within the thecal sac were reviewed. The biologically effective doses (BED) using α/β = 2 Gy for late spinal cord toxicity were calculated and normalized to a 2-Gy equivalent dose (nBED = Gy 2/2). Results: The initial conventional radiotherapy nBED ranged from ∼30 to 50 Gy 2/2 (median ∼40 Gy 2/2). The SBRT reirradiation thecal sac mean P max nBED in the no-RM group was 20.0 Gy 2/2 (95% confidence interval [CI], 10.8-29.2), which was significantly lower than the corresponding 67.4 Gy 2/2 (95% CI, 51.0-83.9) in the RM group. The mean total P max nBED in the no-RM group was 62.3 Gy 2/2 (95% CI, 50.3-74.3), which was significantly lower than the corresponding 105.8 Gy 2/2 (95% CI, 84.3-127.4) in the RM group. The fraction of the total P max nBED accounted for by the SBRT P max nBED for the RM patients ranged from 0.54 to 0.78 and that for the no-RM patients ranged from 0.04 to 0.53. Conclusions: SBRT given at least 5 months after conventional palliative radiotherapy with a reirradiation thecal sac P max nBED of 20-25 Gy 2/2 appears to be safe provided the total P max nBED does not exceed approximately 70 Gy 2/2, and the SBRT thecal sac P max nBED comprises no more than approximately 50% of the total nBED. Copyright © 2012 Elsevier Inc. Printed in the USA. All rights reserved.


An Y.S.,Korea Institute of Radiation and Medical science | Kim M.-R.,Korea Institute of Radiation and Medical science | Lee S.-S.,Korea Institute of Radiation and Medical science | Lee Y.-S.,Ewha Womans University | And 4 more authors.
Experimental Cell Research | Year: 2013

Transforming growth factor-Β1 (TGF-Β1) regulates various biological processes, including differentiation, bone remodeling and angiogenesis, and is particularly important as a regulator of homeostasis and cell growth in normal tissue. Interestingly, some studies have reported that TGF-Β1 induces apoptosis through induction of specific genes, whereas others suggest that TGF-Β1 inhibits apoptosis and facilitates cell survival. Resolving these discrepancies, which may reflect differences in cellular context, is an important research priority. Here, using the parental mink lung epithelial cell line, Mv1Lu, and its derivatives, R1B and DR26, lacking TGF-Β receptors, we investigated the involvement of TGF-Β signaling in the effects of γ-irradiation. We found that canonical TGF-Β signaling played an important role in protecting cells from γ-irradiation. Introduction of functional TGF-Β receptors or constitutively active Smads into R1B and DR26 cell lines reduced DNA fragmentation, Caspase-3 cleavage and γ-H2AX foci formation in γ-irradiated cells. Notably, we also found that de novo protein synthesis was required for the radio-resistant effects of TGF-Β1. Our data thus indicate that TGF-Β1 protected against γ-irradiation, decreasing DNA damage and reducing apoptosis, and thereby enhanced cell survival. © 2012 Elsevier Inc.


An Y.S.,Korea Institute of Radiation and Medical science | Lee E.,Kyung Hee University | Kang M.-H.,Korea Institute of Radiation and Medical science | Hong H.S.,Kyung Hee University | And 4 more authors.
Journal of Cellular Physiology | Year: 2011

The therapeutic use of ionizing radiation (e.g., X-rays and γ-rays) needs to inflict minimal damage on non-target tissue. Recent studies have shown that substance P (SP) mediates multiple activities in various cell types, including cell proliferation, anti-apoptotic responses, and inflammatory processes. The present study investigated the effects of SP on γ-irradiated bone marrow stem cells (BMSCs). In mouse bone marrow extracts, SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression, but attenuated the activation of apoptotic molecules (e.g., p38 and cleaved caspase-3) and down-regulated Bax. We also observed that SP-decreased apoptotic cell death and stimulated cell proliferation in γ-irradiated mouse bone marrow tissues through TUNEL assay and PCNA analysis. To determine how SP affects bone marrow stem cell populations, mouse bone marrow cells were isolated and colony-forming unit (CFU) of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) was estimated. SP-pretreated ones showed higher CFUs of MSC and HSC than untreated ones. Furthermore, when SP was pretreated in cultured human MSC, it significantly decreased apoptotic cells at 48 and 72h after γ-irradiation. Compared with untreated cells, SP-treated human MSCs showed reduced cleavage of apoptotic molecules such as caspase-8, -9, -3, and poly ADP-ribose polymerase (PARP). Thus, our results suggest that SP alleviates γ-radiation-induced damage to mouse BMSCs and human MSCs via regulation of the apoptotic pathway. © 2010 Wiley-Liss, Inc.


Kim M.-R.,Korea Institute of Radiation and Medical science | Lee J.,Korea Institute of Radiation and Medical science | An Y.S.,Korea Institute of Radiation and Medical science | Jin Y.B.,Korea Research Institute of Bioscience and Biotechnology | And 5 more authors.
Molecular Cancer Research | Year: 2015

Several groups have reported that TGFβ1 regulates cellular responses to γ-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFβ1 in cellular responses to γ-irradiation was investigated in detail. The data indicate that TGFβ1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFβ1 was examined. Studies reveal that TGFβ1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFβ1-induced protection against IR. Overall, these data indicate that TGFβ1 facilitates the NHEJ repair process upon γ-irradiation and thereby enhances long-term survival. Implications: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFβ signaling pathway. © 2014 AACR.


PubMed | New York University, Hanyang University, Kyung Hee University, Korea Research Institute of Bioscience and Biotechnology and Korea Institute of Radiation and Medical science
Type: Journal Article | Journal: Molecular cancer research : MCR | Year: 2015

Several groups have reported that TGF1 regulates cellular responses to -irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGF1 in cellular responses to -irradiation was investigated in detail. The data indicate that TGF1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGF1 was examined. Studies reveal that TGF1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGF1-induced protection against IR. Overall, these data indicate that TGF1 facilitates the NHEJ repair process upon -irradiation and thereby enhances long-term survival.These findings provide new insight and a possible approach to controlling genotoxic stress by the TGF signaling pathway.


Lee J.,Korea Institute of Radiation and Medical science | An Y.S.,Korea Institute of Radiation and Medical science | Kim M.-R.,Korea Institute of Radiation and Medical science | Kim Y.-A.,Korea Institute of Radiation and Medical science | And 5 more authors.
Journal of Cellular Biochemistry | Year: 2016

Heat shock protein 90 (HSP90) regulates the stability of various proteins and plays an essential role in cellular homeostasis. Many client proteins of HSP90 are involved in cell growth, survival, and migration; processes that are generally accepted as participants in tumorigenesis. HSP90 is also up-regulated in certain tumors. Indeed, the inhibition of HSP90 is known to be effective in cancer treatment. Recently, studies showed that HSP90 regulates transforming growth factor β1 (TGF-β1)-induced transcription by increasing the stability of the TGF-β receptor. TGF-β signaling also has been implicated in cancer, suggesting the possibility that TGF-β1 and HSP90 function cooperatively during the cancer cell progression. Here in this paper, we investigated the role of HSP90 in TGF-β1-stimulated Mv1Lu cells. Treatment of Mv1Lu cells with the HSP90 inhibitor, 17-allylamino-demethoxy-geldanamycin (17AAG), or transfection with truncated HSP90 (ΔHSP90) significantly reduced TGF-β1-induced cell migration. Pretreatment with 17AAG or transfection with ΔHSP90 also reduced the levels of phosphorylated Smad2 and Smad3. In addition, the HSP90 inhibition interfered the nuclear localization of Smads induced by constitutively active Smad2 (S2EE) or Smad3 (S3EE). We also found that the HSP90 inhibition decreased the protein level of importin-β1 which is known to regulate R-Smad nuclear translocation. These data clearly demonstrate a novel function of HSP90; HSP90 modulates TGF-β signaling by regulating Smads localization. Overall, our data could provide a detailed mechanism linking HSP90 and TGF-β signaling. The extension of our understanding of HSP90 would offer a better strategy for treating cancer. © 2015 Wiley Periodicals, Inc.


PubMed | Catholic Kwandong University, Kyung Hee University and Korea Institute of Radiation and Medical science
Type: Journal Article | Journal: Journal of cellular biochemistry | Year: 2016

Heat shock protein 90 (HSP90) regulates the stability of various proteins and plays an essential role in cellular homeostasis. Many client proteins of HSP90 are involved in cell growth, survival, and migration; processes that are generally accepted as participants in tumorigenesis. HSP90 is also up-regulated in certain tumors. Indeed, the inhibition of HSP90 is known to be effective in cancer treatment. Recently, studies showed that HSP90 regulates transforming growth factor 1 (TGF-1)-induced transcription by increasing the stability of the TGF- receptor. TGF- signaling also has been implicated in cancer, suggesting the possibility that TGF-1 and HSP90 function cooperatively during the cancer cell progression. Here in this paper, we investigated the role of HSP90 in TGF-1-stimulated Mv1Lu cells. Treatment of Mv1Lu cells with the HSP90 inhibitor, 17-allylamino-demethoxy-geldanamycin (17AAG), or transfection with truncated HSP90 (HSP90) significantly reduced TGF-1-induced cell migration. Pretreatment with 17AAG or transfection with HSP90 also reduced the levels of phosphorylated Smad2 and Smad3. In addition, the HSP90 inhibition interfered the nuclear localization of Smads induced by constitutively active Smad2 (S2EE) or Smad3 (S3EE). We also found that the HSP90 inhibition decreased the protein level of importin-1 which is known to regulate R-Smad nuclear translocation. These data clearly demonstrate a novel function of HSP90; HSP90 modulates TGF- signaling by regulating Smads localization. Overall, our data could provide a detailed mechanism linking HSP90 and TGF- signaling. The extension of our understanding of HSP90 would offer a better strategy for treating cancer.


PubMed | Korea Institute of Radiation and Medical science
Type: Journal Article | Journal: Journal of cellular physiology | Year: 2011

The therapeutic use of ionizing radiation (e.g., X-rays and -rays) needs to inflict minimal damage on non-target tissue. Recent studies have shown that substance P (SP) mediates multiple activities in various cell types, including cell proliferation, anti-apoptotic responses, and inflammatory processes. The present study investigated the effects of SP on -irradiated bone marrow stem cells (BMSCs). In mouse bone marrow extracts, SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression, but attenuated the activation of apoptotic molecules (e.g., p38 and cleaved caspase-3) and down-regulated Bax. We also observed that SP-decreased apoptotic cell death and stimulated cell proliferation in -irradiated mouse bone marrow tissues through TUNEL assay and PCNA analysis. To determine how SP affects bone marrow stem cell populations, mouse bone marrow cells were isolated and colony-forming unit (CFU) of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) was estimated. SP-pretreated ones showed higher CFUs of MSC and HSC than untreated ones. Furthermore, when SP was pretreated in cultured human MSC, it significantly decreased apoptotic cells at 48 and 72 h after -irradiation. Compared with untreated cells, SP-treated human MSCs showed reduced cleavage of apoptotic molecules such as caspase-8, -9, -3, and poly ADP-ribose polymerase (PARP). Thus, our results suggest that SP alleviates -radiation-induced damage to mouse BMSCs and human MSCs via regulation of the apoptotic pathway.


PubMed | Korea Institute of Radiation and Medical science
Type: Evaluation Studies | Journal: Experimental cell research | Year: 2013

Transforming growth factor-1 (TGF-1) regulates various biological processes, including differentiation, bone remodeling and angiogenesis, and is particularly important as a regulator of homeostasis and cell growth in normal tissue. Interestingly, some studies have reported that TGF-1 induces apoptosis through induction of specific genes, whereas others suggest that TGF-1 inhibits apoptosis and facilitates cell survival. Resolving these discrepancies, which may reflect differences in cellular context, is an important research priority. Here, using the parental mink lung epithelial cell line, Mv1Lu, and its derivatives, R1B and DR26, lacking TGF- receptors, we investigated the involvement of TGF- signaling in the effects of -irradiation. We found that canonical TGF- signaling played an important role in protecting cells from -irradiation. Introduction of functional TGF- receptors or constitutively active Smads into R1B and DR26 cell lines reduced DNA fragmentation, Caspase-3 cleavage and -H2AX foci formation in -irradiated cells. Notably, we also found that de novo protein synthesis was required for the radio-resistant effects of TGF-1. Our data thus indicate that TGF-1 protected against -irradiation, decreasing DNA damage and reducing apoptosis, and thereby enhanced cell survival.

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