Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear whether signaling pathways triggered by hypoxia contribute to radiation resistance. For example, intratumoral hypoxia can increase hypoxia inducible factor 1 alpha (HIF-1α), which may regulate pathways that contribute to radiation sensitization or radiation resistance. To clarify the role of HIF-1α in regulating tumor response to radiation, we generated a novel genetically engineered mouse model of soft tissue sarcoma with an intact or deleted HIF-1α. Deletion of HIF-1α sensitized primary sarcomas to radiation exposure in vivo. Moreover, cell lines derived from primary sarcomas lacking HIF-1α, or in which HIF-1α was knocked down, had decreased clonogenic survival in vitro, demonstrating that HIF-1α can promote radiation resistance in a cell autonomous manner. In HIF-1α-intact and -deleted sarcoma cells, radiation-induced reactive oxygen species, DNA damage repair and activation of autophagy were similar. However, sarcoma cells lacking HIF-1α had impaired mitochondrial biogenesis and metabolic response after irradiation, which might contribute to radiation resistance. These results show that HIF-1α promotes radiation resistance in a cell autonomous manner.
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1 June 2015
REGULAR ARTICLES|
May 14 2015
HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism
Minsi Zhang;
Minsi Zhang
1
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
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Thomas F. DeLaney;
Thomas F. DeLaney
f Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts; and
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Olga R. Ilkayeva;
Olga R. Ilkayeva
g Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina
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Ki Lui;
Ki Lui
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
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Amanda G. Nichols;
Amanda G. Nichols
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
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Christopher B. Newgard;
Christopher B. Newgard
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
g Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina
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Michael B. Kastan;
Michael B. Kastan
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
d Pediatrics and
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Jeffrey C. Rathmell;
Jeffrey C. Rathmell
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
e Immunology, Duke University Medical Center, Durham, North Carolina;
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Mark W. Dewhirst;
Mark W. Dewhirst
b Radiation Oncology,
c Pathology,
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David G. Kirsch
David G. Kirsch
2
a Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina; Departments of
b Radiation Oncology,
2 Address for correspondence: Duke University Medical Center, Box 91006, Durham, NC 27708; e-mail: david.kirsch@duke.edu.
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Radiat Res (2015) 183 (6): 594–609.
Article history
Received:
January 07 2015
Accepted:
April 13 2015
Citation
Minsi Zhang, Qiong Qiu, Zhizhong Li, Mohit Sachdeva, Hooney Min, Diana M. Cardona, Thomas F. DeLaney, Tracy Han, Yan Ma, Lixia Luo, Olga R. Ilkayeva, Ki Lui, Amanda G. Nichols, Christopher B. Newgard, Michael B. Kastan, Jeffrey C. Rathmell, Mark W. Dewhirst, David G. Kirsch; HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism. Radiat Res 1 June 2015; 183 (6): 594–609. doi: https://doi.org/10.1667/RR14016.1
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