Page 99 - 2014 Printable Abstract Book
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metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with
decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical
investigation of RT and DSF as a novel combinatorial treatment for breast cancer.
(S2903) The role of the mitochondrial enzyme SOD2 in adaptive responses. Richard C. Miller, University
of Chicago, Chicago, IL
Historically, studies on the damaging effects of ionizing radiation have been focused on damage
and repair of nuclear DNA. Recently, the role of mitochondria as targets for radiation damage contributing
to the overall cellular response to radiation exposure has been recognized. Central to the radiation-
induced damage response of the mitochondria is the mitochondrial enzyme manganese superoxide
dismutase (SOD2) whose primary function is to convert radiation-induced super oxide into hydrogen
peroxide. Hydrogen peroxide is then converted through the action of glutathione peroxidase and/or
catalase to water and oxygen, thus eliminating the highly reactive and potentially damaging superoxide
radical. SOD2 levels can be induced through the action of very low doses of ionizing radiation that initiate
a cascade of events mediated by TNFα signaling leading to NFκB activation, and induction of elevated
SOD2 gene expression. These events culminate in the significant elevation of SOD2 intra-mitochondrial
protein levels which can confer an elevated overall cellular resistance to the damaging effects of ionizing
radiation if exposure to a high dose of ionizing radiation occurs at this time. This process is an underlying
mechanism for the phenomenon identified as the adaptive response. The roles of TNFα signaling, NFκB
activation and induced elevated SOD2 gene expression in the development of an adaptive response will
be demonstrated and discussed utilizing data from well characterized mammalian cell lines, both wild
type and matched engineered for defects in TNF receptors R1 and R2 or stably transfected with a mutant
IκBα construct inhibiting NFκB activation. Cell survival and micronuclei formation will be utilized as the
endpoints to demonstrate the presence and relative magnitude of the SOD2-mediated adaptive response.
This work was supported by NIH/NCI grant R01 CA 132998 and DOE Low Dose Program/Project Grant DE-
SC0001271.
(S2904) NF-kB-initiated mitochondrial homeostasis in radiation-induced adaptive response.
Jian Jian Li, Purdue University, West Lafayette, IN
Tumor radioresistance remains to be one of the major challenges for further improving the
efficacy of anti-cancer radiotherapy. Data generated by in vitro and in vivo models and clinical samples
indicate that irradiated mammalian cells can induce a prosurvival signaling network controlled by the
transcription factor NF-κB, a well-defined factor in regulating inflammation and immunologic responses.
We found that a group of NF-κB targeted prosurvival factors including MKP-1, HER2, STAT3 and cell cycle
complexes, Cyclin D1/CDK4 and Cyclin B1/CDK1 can enhance cell survival by regulation of mitochondrial
functions via phosphorylation of their mitochondrial targets. These include: a) CyclinB1/D1-CDK1/4
complexes-mediated MnSOD phosphorylation and MnSOD enzymatic activation without requirement of
enhanced SOD2 gene upregulation; and b) NF-κB-enhanced HER2 promoter activation and HER2
overexpression in turn activates STAT3 via two different residue phosphorylation, an oncogenic
transcription factor, that can then relocate to nucleus and mitochondria to boost mitochondrial
respiration for DNA repair and cell survival. In addition, NF-κB is responsible for radiation-induced CD47,
97 | P a g e
decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical
investigation of RT and DSF as a novel combinatorial treatment for breast cancer.
(S2903) The role of the mitochondrial enzyme SOD2 in adaptive responses. Richard C. Miller, University
of Chicago, Chicago, IL
Historically, studies on the damaging effects of ionizing radiation have been focused on damage
and repair of nuclear DNA. Recently, the role of mitochondria as targets for radiation damage contributing
to the overall cellular response to radiation exposure has been recognized. Central to the radiation-
induced damage response of the mitochondria is the mitochondrial enzyme manganese superoxide
dismutase (SOD2) whose primary function is to convert radiation-induced super oxide into hydrogen
peroxide. Hydrogen peroxide is then converted through the action of glutathione peroxidase and/or
catalase to water and oxygen, thus eliminating the highly reactive and potentially damaging superoxide
radical. SOD2 levels can be induced through the action of very low doses of ionizing radiation that initiate
a cascade of events mediated by TNFα signaling leading to NFκB activation, and induction of elevated
SOD2 gene expression. These events culminate in the significant elevation of SOD2 intra-mitochondrial
protein levels which can confer an elevated overall cellular resistance to the damaging effects of ionizing
radiation if exposure to a high dose of ionizing radiation occurs at this time. This process is an underlying
mechanism for the phenomenon identified as the adaptive response. The roles of TNFα signaling, NFκB
activation and induced elevated SOD2 gene expression in the development of an adaptive response will
be demonstrated and discussed utilizing data from well characterized mammalian cell lines, both wild
type and matched engineered for defects in TNF receptors R1 and R2 or stably transfected with a mutant
IκBα construct inhibiting NFκB activation. Cell survival and micronuclei formation will be utilized as the
endpoints to demonstrate the presence and relative magnitude of the SOD2-mediated adaptive response.
This work was supported by NIH/NCI grant R01 CA 132998 and DOE Low Dose Program/Project Grant DE-
SC0001271.
(S2904) NF-kB-initiated mitochondrial homeostasis in radiation-induced adaptive response.
Jian Jian Li, Purdue University, West Lafayette, IN
Tumor radioresistance remains to be one of the major challenges for further improving the
efficacy of anti-cancer radiotherapy. Data generated by in vitro and in vivo models and clinical samples
indicate that irradiated mammalian cells can induce a prosurvival signaling network controlled by the
transcription factor NF-κB, a well-defined factor in regulating inflammation and immunologic responses.
We found that a group of NF-κB targeted prosurvival factors including MKP-1, HER2, STAT3 and cell cycle
complexes, Cyclin D1/CDK4 and Cyclin B1/CDK1 can enhance cell survival by regulation of mitochondrial
functions via phosphorylation of their mitochondrial targets. These include: a) CyclinB1/D1-CDK1/4
complexes-mediated MnSOD phosphorylation and MnSOD enzymatic activation without requirement of
enhanced SOD2 gene upregulation; and b) NF-κB-enhanced HER2 promoter activation and HER2
overexpression in turn activates STAT3 via two different residue phosphorylation, an oncogenic
transcription factor, that can then relocate to nucleus and mitochondria to boost mitochondrial
respiration for DNA repair and cell survival. In addition, NF-κB is responsible for radiation-induced CD47,
97 | P a g e
