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Girdhar G. Sharma - One of the best experts on this subject based on the ideXlab platform.
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Transient PP2A inhibition alleviates Normal tissue Stem Cell susceptibility to Cell death during radiotherapy
Cell Death & Disease, 2018Co-Authors: Maria Rita Fabbrizi, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Girdhar G. SharmaAbstract:Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced Stem Cell depletion, diminished regenerative capacity, and accelerated aging. Stem Cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-Stem Cells. We performed genomic discovery research to compare Stem Cells to differentiated Cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in Stem Cells. PP2A dephosphorylates pATM, γH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer Cells, the role of PP2A in Normal Stem Cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in Stem Cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of Stem Cells, without affecting differentiated non-Stem and cancer Cells. PP2Ai-mediated Stem Cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic Stem Cells.
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Molecular and epigenetic regulatory mechanisms of Normal Stem Cell radiosensitivity
Nature Publishing Group, 2018Co-Authors: Maria Rita Fabbrizi, Cheri L. Zobel, Dennis E. Hallahan, Kacie E. Warshowsky, Girdhar G. SharmaAbstract:Abstract Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural Stem/progenitor Cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are common side effects in patients with gastrointestinal tumors and are believed to be caused by intestinal Stem Cell drop out. Hematopoietic Stem Cell transplantation is currently used to reinstate blood production in leukemia patients and pre-clinical treatments show promising results in other organs such as the skin and kidney, but ethical issues and logistic problems make this route difficult to follow. An alternative way to restore the injured tissue is to preserve the Stem Cell pool located in that specific tissue/organ niche, but Stem Cell response to ionizing radiation is inadequately understood at the molecular mechanistic level. Although embryonic and fetal hypersensity to IR has been very well known for many decades, research on embryonic Stem Cell models in culture concerning molecular mechanisms have been largely inconclusive and often in contradiction of the in vivo observations. This review will summarize the latest discoveries on Stem Cell radiosensitivity, highlighting the possible molecular and epigenetic mechanism(s) involved in DNA damage response and programmed Cell death after ionizing radiation therapy specific to Normal Stem Cells. Finally, we will analyze the possible contribution of Stem Cell-specific chromatin’s epigenetic constitution in promoting Normal Stem Cell radiosensitivity
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Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on Normal Stem Cell radioresponses.
Molecular biology of the cell, 2016Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of Normal Stem Cell populations compared with non-Stem Cells within several radiosensitive tissue niches and culture models. We found that these Stem Cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas Stem Cells exhibit reduced ATM activation and ionizing radiation-induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (γH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in Stem Cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in Stem Cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to Stem Cell radiosensitivity. These results establish that unique epigenetic landscapes affect Cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various Normal Stem Cell populations, identifying potential molecular targets for pharmacological radioprotection of Stem Cells and hopefully improving the efficacy of future cancer treatment.
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Abstract 3300: Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity
Tumor Biology, 2015Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Side effects resulting from ionizing radiation (IR) during cancer radiotherapy often involve Normal tissue injury including depletion of tissue regenerative capacity. Utilizing multiple in vivo tissue niches and Cell culture models, we demonstrate that Normal Stem Cells are highly radiosensitive while differentiated progeny are radioresistant, and IR-induced apoptosis of Stem Cells is observed broadly throughout the Cell cycle independent of proliferation status. Our study demonstrates that Normal Stem Cells fail to activate the DDR, do not display IR-induced foci in vivo as well as in culture, and exhibit severely attenuated DNA repair. Despite Normal sensing of DNA breaks, recruitment/ retention of repair factors at DNA break sites is repressed in Stem Cells. Stem Cells are unable to eliminate constitutive phosphorylation of H2AX-Y142 around break sites, abetting Stem Cells toward an apoptotic instead of repair pathway. The abrogated DDR in Normal Stem Cells is associated with a constitutively enhanced histone-3 lysine-56 acetylation, which epigenetically contributes to muted retention of repair factors. Reinforced PP2A phosphatase expression was also identified as substantial regulators of Stem Cell radiosensitivity and transient inhibition of phosphatase activity restores Stem Cell survival. We thus identify pluralistic interacting molecular and epigenetic mechanisms that collectively control and impart IR hypersensitive phenotype to the Normal Stem Cells. These insights will be crucial in development of prevention and intervention therapeutic strategies to minimize IR-induced Stem Cell dropout and increase the efficacy of radiotherapy. Citation Format: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma. Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3300. doi:10.1158/1538-7445.AM2015-3300
Cheri L. Zobel - One of the best experts on this subject based on the ideXlab platform.
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Transient PP2A inhibition alleviates Normal tissue Stem Cell susceptibility to Cell death during radiotherapy
Cell Death & Disease, 2018Co-Authors: Maria Rita Fabbrizi, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Girdhar G. SharmaAbstract:Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced Stem Cell depletion, diminished regenerative capacity, and accelerated aging. Stem Cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-Stem Cells. We performed genomic discovery research to compare Stem Cells to differentiated Cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in Stem Cells. PP2A dephosphorylates pATM, γH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer Cells, the role of PP2A in Normal Stem Cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in Stem Cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of Stem Cells, without affecting differentiated non-Stem and cancer Cells. PP2Ai-mediated Stem Cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic Stem Cells.
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Molecular and epigenetic regulatory mechanisms of Normal Stem Cell radiosensitivity
Nature Publishing Group, 2018Co-Authors: Maria Rita Fabbrizi, Cheri L. Zobel, Dennis E. Hallahan, Kacie E. Warshowsky, Girdhar G. SharmaAbstract:Abstract Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural Stem/progenitor Cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are common side effects in patients with gastrointestinal tumors and are believed to be caused by intestinal Stem Cell drop out. Hematopoietic Stem Cell transplantation is currently used to reinstate blood production in leukemia patients and pre-clinical treatments show promising results in other organs such as the skin and kidney, but ethical issues and logistic problems make this route difficult to follow. An alternative way to restore the injured tissue is to preserve the Stem Cell pool located in that specific tissue/organ niche, but Stem Cell response to ionizing radiation is inadequately understood at the molecular mechanistic level. Although embryonic and fetal hypersensity to IR has been very well known for many decades, research on embryonic Stem Cell models in culture concerning molecular mechanisms have been largely inconclusive and often in contradiction of the in vivo observations. This review will summarize the latest discoveries on Stem Cell radiosensitivity, highlighting the possible molecular and epigenetic mechanism(s) involved in DNA damage response and programmed Cell death after ionizing radiation therapy specific to Normal Stem Cells. Finally, we will analyze the possible contribution of Stem Cell-specific chromatin’s epigenetic constitution in promoting Normal Stem Cell radiosensitivity
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Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on Normal Stem Cell radioresponses.
Molecular biology of the cell, 2016Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of Normal Stem Cell populations compared with non-Stem Cells within several radiosensitive tissue niches and culture models. We found that these Stem Cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas Stem Cells exhibit reduced ATM activation and ionizing radiation-induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (γH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in Stem Cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in Stem Cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to Stem Cell radiosensitivity. These results establish that unique epigenetic landscapes affect Cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various Normal Stem Cell populations, identifying potential molecular targets for pharmacological radioprotection of Stem Cells and hopefully improving the efficacy of future cancer treatment.
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Abstract 3300: Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity
Tumor Biology, 2015Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Side effects resulting from ionizing radiation (IR) during cancer radiotherapy often involve Normal tissue injury including depletion of tissue regenerative capacity. Utilizing multiple in vivo tissue niches and Cell culture models, we demonstrate that Normal Stem Cells are highly radiosensitive while differentiated progeny are radioresistant, and IR-induced apoptosis of Stem Cells is observed broadly throughout the Cell cycle independent of proliferation status. Our study demonstrates that Normal Stem Cells fail to activate the DDR, do not display IR-induced foci in vivo as well as in culture, and exhibit severely attenuated DNA repair. Despite Normal sensing of DNA breaks, recruitment/ retention of repair factors at DNA break sites is repressed in Stem Cells. Stem Cells are unable to eliminate constitutive phosphorylation of H2AX-Y142 around break sites, abetting Stem Cells toward an apoptotic instead of repair pathway. The abrogated DDR in Normal Stem Cells is associated with a constitutively enhanced histone-3 lysine-56 acetylation, which epigenetically contributes to muted retention of repair factors. Reinforced PP2A phosphatase expression was also identified as substantial regulators of Stem Cell radiosensitivity and transient inhibition of phosphatase activity restores Stem Cell survival. We thus identify pluralistic interacting molecular and epigenetic mechanisms that collectively control and impart IR hypersensitive phenotype to the Normal Stem Cells. These insights will be crucial in development of prevention and intervention therapeutic strategies to minimize IR-induced Stem Cell dropout and increase the efficacy of radiotherapy. Citation Format: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma. Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3300. doi:10.1158/1538-7445.AM2015-3300
Dennis E. Hallahan - One of the best experts on this subject based on the ideXlab platform.
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Transient PP2A inhibition alleviates Normal tissue Stem Cell susceptibility to Cell death during radiotherapy
Cell Death & Disease, 2018Co-Authors: Maria Rita Fabbrizi, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Girdhar G. SharmaAbstract:Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced Stem Cell depletion, diminished regenerative capacity, and accelerated aging. Stem Cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-Stem Cells. We performed genomic discovery research to compare Stem Cells to differentiated Cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in Stem Cells. PP2A dephosphorylates pATM, γH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer Cells, the role of PP2A in Normal Stem Cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in Stem Cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of Stem Cells, without affecting differentiated non-Stem and cancer Cells. PP2Ai-mediated Stem Cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic Stem Cells.
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Molecular and epigenetic regulatory mechanisms of Normal Stem Cell radiosensitivity
Nature Publishing Group, 2018Co-Authors: Maria Rita Fabbrizi, Cheri L. Zobel, Dennis E. Hallahan, Kacie E. Warshowsky, Girdhar G. SharmaAbstract:Abstract Ionizing radiation (IR) therapy is a major cancer treatment modality and an indispensable auxiliary treatment for primary and metastatic cancers, but invariably results in debilitating organ dysfunctions. IR-induced depletion of neural Stem/progenitor Cells in the subgranular zone of the dentate gyrus in the hippocampus where neurogenesis occurs is considered largely responsible for deficiencies such as learning, memory, and spatial information processing in patients subjected to cranial irradiation. Similarly, IR therapy-induced intestinal injuries such as diarrhea and malabsorption are common side effects in patients with gastrointestinal tumors and are believed to be caused by intestinal Stem Cell drop out. Hematopoietic Stem Cell transplantation is currently used to reinstate blood production in leukemia patients and pre-clinical treatments show promising results in other organs such as the skin and kidney, but ethical issues and logistic problems make this route difficult to follow. An alternative way to restore the injured tissue is to preserve the Stem Cell pool located in that specific tissue/organ niche, but Stem Cell response to ionizing radiation is inadequately understood at the molecular mechanistic level. Although embryonic and fetal hypersensity to IR has been very well known for many decades, research on embryonic Stem Cell models in culture concerning molecular mechanisms have been largely inconclusive and often in contradiction of the in vivo observations. This review will summarize the latest discoveries on Stem Cell radiosensitivity, highlighting the possible molecular and epigenetic mechanism(s) involved in DNA damage response and programmed Cell death after ionizing radiation therapy specific to Normal Stem Cells. Finally, we will analyze the possible contribution of Stem Cell-specific chromatin’s epigenetic constitution in promoting Normal Stem Cell radiosensitivity
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Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on Normal Stem Cell radioresponses.
Molecular biology of the cell, 2016Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of Normal Stem Cell populations compared with non-Stem Cells within several radiosensitive tissue niches and culture models. We found that these Stem Cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas Stem Cells exhibit reduced ATM activation and ionizing radiation-induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (γH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in Stem Cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in Stem Cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to Stem Cell radiosensitivity. These results establish that unique epigenetic landscapes affect Cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various Normal Stem Cell populations, identifying potential molecular targets for pharmacological radioprotection of Stem Cells and hopefully improving the efficacy of future cancer treatment.
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Abstract 3300: Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity
Tumor Biology, 2015Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Side effects resulting from ionizing radiation (IR) during cancer radiotherapy often involve Normal tissue injury including depletion of tissue regenerative capacity. Utilizing multiple in vivo tissue niches and Cell culture models, we demonstrate that Normal Stem Cells are highly radiosensitive while differentiated progeny are radioresistant, and IR-induced apoptosis of Stem Cells is observed broadly throughout the Cell cycle independent of proliferation status. Our study demonstrates that Normal Stem Cells fail to activate the DDR, do not display IR-induced foci in vivo as well as in culture, and exhibit severely attenuated DNA repair. Despite Normal sensing of DNA breaks, recruitment/ retention of repair factors at DNA break sites is repressed in Stem Cells. Stem Cells are unable to eliminate constitutive phosphorylation of H2AX-Y142 around break sites, abetting Stem Cells toward an apoptotic instead of repair pathway. The abrogated DDR in Normal Stem Cells is associated with a constitutively enhanced histone-3 lysine-56 acetylation, which epigenetically contributes to muted retention of repair factors. Reinforced PP2A phosphatase expression was also identified as substantial regulators of Stem Cell radiosensitivity and transient inhibition of phosphatase activity restores Stem Cell survival. We thus identify pluralistic interacting molecular and epigenetic mechanisms that collectively control and impart IR hypersensitive phenotype to the Normal Stem Cells. These insights will be crucial in development of prevention and intervention therapeutic strategies to minimize IR-induced Stem Cell dropout and increase the efficacy of radiotherapy. Citation Format: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma. Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3300. doi:10.1158/1538-7445.AM2015-3300
Toshio Suda - One of the best experts on this subject based on the ideXlab platform.
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regulation of reactive oxygen species in Stem Cells and cancer Stem Cells
Journal of Cellular Physiology, 2012Co-Authors: Chiharu I. Kobayashi, Toshio SudaAbstract:Stem Cells are defined by their ability to self-renew and their multi-potent differentiation capacity. As such, Stem Cells maintain tissue homeostasis throughout the life of a multiCellular organism. Aerobic metabolism, while enabling efficient energy production, also generates reactive oxygen species (ROS), which damage Cellular components. Until recently, the focus in Stem Cell biology has been on the adverse effects of ROS, particularly the damaging effects of ROS accumulation on tissue aging and the development of cancer, and various anti-oxidative and anti-stress mechanisms of Stem Cells have been characterized. However, it has become increasingly clear that, in some cases, redox status plays an important role in Stem Cell maintenance, i.e., regulation of the Cell cycle. An active area of current research is redox regulation in various cancer Stem Cells, the malignant counterparts of Normal Stem Cells that are viewed as good targets of cancer therapy. In contrast to cancer Cells, in which ROS levels are increased, some cancer Stem Cells maintain low ROS levels, exhibiting redox patterns that are similar to the corresponding Normal Stem Cell. To fully elucidate the mechanisms involved in Stem Cell maintenance and to effectively target cancer Stem Cells, it is essential to understand ROS regulatory mechanisms in these different Cell types. Here, the mechanisms of redox regulation in Normal Stem Cells, cancer Cells, and cancer Stem Cells are reviewed. J. Cell. Physiol. 227: 421–430, 2012. © 2011 Wiley Periodicals, Inc.
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Regulation of reactive oxygen species in Stem Cells and cancer Stem Cells.
Journal of Cellular Physiology, 2011Co-Authors: Chiharu I. Kobayashi, Toshio SudaAbstract:Stem Cells are defined by their ability to self-renew and their multi-potent differentiation capacity. As such, Stem Cells maintain tissue homeostasis throughout the life of a multiCellular organism. Aerobic metabolism, while enabling efficient energy production, also generates reactive oxygen species (ROS), which damage Cellular components. Until recently, the focus in Stem Cell biology has been on the adverse effects of ROS, particularly the damaging effects of ROS accumulation on tissue aging and the development of cancer, and various anti-oxidative and anti-stress mechanisms of Stem Cells have been characterized. However, it has become increasingly clear that, in some cases, redox status plays an important role in Stem Cell maintenance, i.e., regulation of the Cell cycle. An active area of current research is redox regulation in various cancer Stem Cells, the malignant counterparts of Normal Stem Cells that are viewed as good targets of cancer therapy. In contrast to cancer Cells, in which ROS levels are increased, some cancer Stem Cells maintain low ROS levels, exhibiting redox patterns that are similar to the corresponding Normal Stem Cell. To fully elucidate the mechanisms involved in Stem Cell maintenance and to effectively target cancer Stem Cells, it is essential to understand ROS regulatory mechanisms in these different Cell types. Here, the mechanisms of redox regulation in Normal Stem Cells, cancer Cells, and cancer Stem Cells are reviewed.
Barbara Meyer - One of the best experts on this subject based on the ideXlab platform.
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Transient PP2A inhibition alleviates Normal tissue Stem Cell susceptibility to Cell death during radiotherapy
Cell Death & Disease, 2018Co-Authors: Maria Rita Fabbrizi, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Girdhar G. SharmaAbstract:Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced Stem Cell depletion, diminished regenerative capacity, and accelerated aging. Stem Cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-Stem Cells. We performed genomic discovery research to compare Stem Cells to differentiated Cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in Stem Cells. PP2A dephosphorylates pATM, γH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer Cells, the role of PP2A in Normal Stem Cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in Stem Cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of Stem Cells, without affecting differentiated non-Stem and cancer Cells. PP2Ai-mediated Stem Cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic Stem Cells.
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Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on Normal Stem Cell radioresponses.
Molecular biology of the cell, 2016Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of Normal Stem Cell populations compared with non-Stem Cells within several radiosensitive tissue niches and culture models. We found that these Stem Cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas Stem Cells exhibit reduced ATM activation and ionizing radiation-induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (γH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in Stem Cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in Stem Cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to Stem Cell radiosensitivity. These results establish that unique epigenetic landscapes affect Cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various Normal Stem Cell populations, identifying potential molecular targets for pharmacological radioprotection of Stem Cells and hopefully improving the efficacy of future cancer treatment.
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Abstract 3300: Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity
Tumor Biology, 2015Co-Authors: Keith M. Jacobs, Barbara Meyer, Sandeep Misri, Suyash Raj, Cheri L. Zobel, Dennis E. Hallahan, Barry P. Sleckman, Girdhar G. SharmaAbstract:Side effects resulting from ionizing radiation (IR) during cancer radiotherapy often involve Normal tissue injury including depletion of tissue regenerative capacity. Utilizing multiple in vivo tissue niches and Cell culture models, we demonstrate that Normal Stem Cells are highly radiosensitive while differentiated progeny are radioresistant, and IR-induced apoptosis of Stem Cells is observed broadly throughout the Cell cycle independent of proliferation status. Our study demonstrates that Normal Stem Cells fail to activate the DDR, do not display IR-induced foci in vivo as well as in culture, and exhibit severely attenuated DNA repair. Despite Normal sensing of DNA breaks, recruitment/ retention of repair factors at DNA break sites is repressed in Stem Cells. Stem Cells are unable to eliminate constitutive phosphorylation of H2AX-Y142 around break sites, abetting Stem Cells toward an apoptotic instead of repair pathway. The abrogated DDR in Normal Stem Cells is associated with a constitutively enhanced histone-3 lysine-56 acetylation, which epigenetically contributes to muted retention of repair factors. Reinforced PP2A phosphatase expression was also identified as substantial regulators of Stem Cell radiosensitivity and transient inhibition of phosphatase activity restores Stem Cell survival. We thus identify pluralistic interacting molecular and epigenetic mechanisms that collectively control and impart IR hypersensitive phenotype to the Normal Stem Cells. These insights will be crucial in development of prevention and intervention therapeutic strategies to minimize IR-induced Stem Cell dropout and increase the efficacy of radiotherapy. Citation Format: Keith M. Jacobs, Sandeep Misri, Barbara Meyer, Suyash Raj, Cheri L. Zobel, Barry P. Sleckman, Dennis E. Hallahan, Girdhar G. Sharma. Concerted epigenetic and signaling mechanisms regulate Normal Stem Cell radiosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3300. doi:10.1158/1538-7445.AM2015-3300
