This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Papandreou, I. Articles by Denko, N. C. Search for Related Content PubMed PubMed Citation Articles by Papandreou, I. Articles by Denko, N. C.

Anoxia Is Necessary for Tumor Cell Toxicity Caused by a Low-Oxygen Environment

Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California

Requests for reprints: Nicholas C. Denko, Room 1245, CCSR South, 269 Campus Drive, Stanford, CA 94305. Phone: 650-724-5066; Fax: 650-723-7382; E-mail: ndenko{at}cmgm.stanford.edu.

Cells exposed to oxygen deprivation in vitro have been shown to reduce proliferation and/or engage in programmed cell death. There is considerable controversy in the literature as to the role of hypoxia-inducible factor-1 (HIF-1) and HIF-1 target genes in initiating these responses. We therefore examined the oxygen dependence and the role of the hypoxia-responsive transcription factor HIF-1 in making the cellular death decision. Oxygen concentrations as low as 0.5% did not alter the growth of HIF-1–proficient or HIF-1–deficient murine fibroblasts, or human tumor cells, despite the appropriate induction of HIF-1 target genes. Severe hypoxia (<0.01% oxygen) did induced apoptosis, resulting in decreased colony formation, chromatin condensation, DNA fragmentation, and caspase activation but also independent of HIF1 status. Transcriptional induction of HIF-1–dependent genes putatively involved in cell death like BNip3 and BNip3L was therefore disassociated from hypoxia-dependent toxicity. Likewise, forced overexpression of a nondegradable form of HIF-1 in several human tumor cell lines was not sufficient to induce apoptosis under normoxic conditions. Taken together, these findings indicate that additional molecular events are triggered by anoxia in a HIF-1–independent manner, and these changes are necessary for cell death observed in low-oxygen environments.

This article has been cited by other articles:

				J. Chen, M. Kobayashi, S. Darmanin, Y. Qiao, C. Gully, R. Zhao, S. Kondo, H. Wang, H. Wang, S.-C. J. Yeung, et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation Am. J. Pathol., July 1, 2009; 175(1): 400 - 411. [Abstract] [Full Text] [PDF]

				G. Bellot, R. Garcia-Medina, P. Gounon, J. Chiche, D. Roux, J. Pouyssegur, and N. M. Mazure Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains Mol. Cell. Biol., May 15, 2009; 29(10): 2570 - 2581. [Abstract] [Full Text] [PDF]

				M. Scortegagna, R. J. Martin, R. D. Kladney, R. G. Neumann, and J. M. Arbeit Hypoxia-Inducible Factor-1{alpha} Suppresses Squamous Carcinogenic Progression and Epithelial-Mesenchymal Transition Cancer Res., March 15, 2009; 69(6): 2638 - 2646. [Abstract] [Full Text] [PDF]

				M. Verras, I. Papandreou, A. L. Lim, and N. C. Denko Tumor Hypoxia Blocks Wnt Processing and Secretion through the Induction of Endoplasmic Reticulum Stress Mol. Cell. Biol., December 1, 2008; 28(23): 7212 - 7224. [Abstract] [Full Text] [PDF]

				L. Liu, D. R. Wise, J. A. Diehl, and M. C. Simon Hypoxic Reactive Oxygen Species Regulate the Integrated Stress Response and Cell Survival J. Biol. Chem., November 7, 2008; 283(45): 31153 - 31162. [Abstract] [Full Text] [PDF]

				E. Favaro, G. Nardo, L. Persano, M. Masiero, L. Moserle, R. Zamarchi, E. Rossi, G. Esposito, M. Plebani, U. Sattler, et al. Hypoxia Inducible Factor-1{alpha} Inactivation Unveils a Link between Tumor Cell Metabolism and Hypoxia-Induced Cell Death Am. J. Pathol., October 1, 2008; 173(4): 1186 - 1201. [Abstract] [Full Text] [PDF]

				R. G Bristow Hypoxia, DNA Repair, and Genetic Instability Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 287 - 291. [Abstract] [Full Text] [PDF]

				N. Chan, M. Koritzinsky, H. Zhao, R. Bindra, P. M. Glazer, S. Powell, A. Belmaaza, B. Wouters, and R. G. Bristow Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance Cancer Res., January 15, 2008; 68(2): 605 - 614. [Abstract] [Full Text] [PDF]

				K. Tracy, B. C. Dibling, B. T. Spike, J. R. Knabb, P. Schumacker, and K. F. Macleod BNIP3 Is an RB/E2F Target Gene Required for Hypoxia-Induced Autophagy Mol. Cell. Biol., September 1, 2007; 27(17): 6229 - 6242. [Abstract] [Full Text] [PDF]

				R. A. Cairns, I. Papandreou, P. D. Sutphin, and N. C. Denko Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy PNAS, May 29, 2007; 104(22): 9445 - 9450. [Abstract] [Full Text] [PDF]

				T. Rzymski and A. L. Harris The Unfolded Protein Response and Integrated Stress Response to Anoxia Clin. Cancer Res., May 1, 2007; 13(9): 2537 - 2540. [Abstract] [Full Text] [PDF]

				H. Cui, S. Darmanin, M. Natsuisaka, T. Kondo, M. Asaka, M. Shindoh, F. Higashino, J. Hamuro, F. Okada, M. Kobayashi, et al. Enhanced Expression of Asparagine Synthetase under Glucose-Deprived Conditions Protects Pancreatic Cancer Cells from Apoptosis Induced by Glucose Deprivation and Cisplatin Cancer Res., April 1, 2007; 67(7): 3345 - 3355. [Abstract] [Full Text] [PDF]

				J. K. Brunelle, E. H. Shroff, H. Perlman, A. Strasser, C. T. Moraes, R. A. Flavell, N. N. Danial, B. Keith, C. B. Thompson, and N. S. Chandel Loss of Mcl-1 Protein and Inhibition of Electron Transport Chain Together Induce Anoxic Cell Death Mol. Cell. Biol., February 15, 2007; 27(4): 1222 - 1235. [Abstract] [Full Text] [PDF]

				E. Y. Tan, L. Campo, C. Han, H. Turley, F. Pezzella, K. C. Gatter, A. L. Harris, and S. B. Fox BNIP3 as a Progression Marker in Primary Human Breast Cancer; Opposing Functions in In situ Versus Invasive Cancer Clin. Cancer Res., January 15, 2007; 13(2): 467 - 474. [Abstract] [Full Text] [PDF]

				E. M. Hammond, D. J. Mandell, A. Salim, A. J. Krieg, T. M. Johnson, H. A. Shirazi, L. D. Attardi, and A. J. Giaccia Genome-Wide Analysis of p53 under Hypoxic Conditions. Mol. Cell. Biol., May 1, 2006; 26(9): 3492 - 3504. [Abstract] [Full Text] [PDF]