Impact of cyclic hypoxia on HIF-1a regulation in endothelial cells: new insights for anti-tumor treatments

[en] Impact of cyclic hypoxia on HIF-1alpha regulation in endothelial cells - new insights for anti-tumor treatments.Martinive P, Defresne F, Quaghebeur E, Daneau G, Crokart N, Grégoire V, Gallez B, Dessy C, Feron O. Unit of Pharmacology and Therapeutics, Université catholique de Louvain, Brussels, Belgium. Heterogeneities in tumor blood flow are associated with cyclic changes in pO(2) or cyclic hypoxia. A major difference from O(2) diffusion-limited or chronic hypoxia is that the tumor vasculature itself may be directly influenced by the fluctuating hypoxic environment, and the reoxygenation phases complicate the usual hypoxia-induced phenotypic pattern. Here, we determined the cyclic hypoxia-driven pathways that modulate hypoxia inducible factor (HIF)-1alpha abundance in endothelial cells to identify possible therapeutic targets. We found that exposure of endothelial cells to cycles of hypoxia/reoxygenation led to accumulation of HIF-1alpha during the hypoxic periods and the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK) and endothelial nitric oxide synthase (eNOS) during the reoxygenation phases. We identified stimulation of mitochondrial respiration and activation of the phosphoinositide-3 kinase (PI3K)/Akt pathway during intervening reoxygenation periods as major triggers of the stabilization of HIF-1alpha. We also found that the NOS inhibitor nitro-l-arginine methyl ester further stimulated the cyclic hypoxia-driven HIF-1alpha accumulation and the associated gain in endothelial cell survival, thereby mirroring the effects of a PI3K/Akt inhibitor. However, combination of both drugs resulted in a net reduction in HIF-1alpha and a dramatic in decrease in endothelial cell survival. In conclusion, this study identified cyclic hypoxia, as reported in many tumor types, as a unique biological challenge for endothelial cells that promotes their survival in a HIF-1alpha-dependent manner through phenotypic alterations occurring during the reoxygenation periods. These observations also indicate the potential of combining Akt-targeting drugs with anti-angiogenic drugs, in particular those interfering with the NO pathway. PMID: 19077164 [PubMed - as supplied by publisher

Disciplines :

Oncology

Author, co-author :

Martinive, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > Radiothérapie

Language :

English

Title :

Impact of cyclic hypoxia on HIF-1a regulation in endothelial cells: new insights for anti-tumor treatments

Publication date :

10 December 2008

Journal title :

FEBS Journal

ISSN :

1742-464X

eISSN :

1742-4658

Publisher :

Blackwell Publishing, Oxford, United Kingdom

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 05 August 2009

Statistics

Number of views

127 (10 by ULiège)

Number of downloads

233 (5 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3, 721 732.
Michiels C (2004) Physiological and pathological responses to hypoxia. Am J Pathol 164, 1875 1882.
Pouyssegur J, Dayan F Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437 443.
Vincent KA, Feron O Kelly RA (2002) Harnessing the response to tissue hypoxia: HIF-1 α and therapeutic angiogenesis. Trends Cardiovasc Med 12, 362 367.
Schofield CJ Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5, 343 354.
Zhou J Brune B (2006) Cytokines and hormones in the regulation of hypoxia inducible factor-1α (HIF-1α). Cardiovasc Hematol Agents Med Chem 4, 189 197.
Hagen T, Taylor CT, Lam F Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science 302, 1975 1978.
Metzen E, Zhou J, Jelkmann W, Fandrey J Brune B (2003) Nitric oxide impairs normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases. Mol Biol Cell 14, 3470 3481.
Li F, Sonveaux P, Rabbani ZN, Liu S, Yan B, Huang Q, Vujaskovic Z, Dewhirst MW Li CY (2007) Regulation of HIF-1α stability through S-nitrosylation. Mol Cell 26, 63 74.
Quintero M, Brennan PA, Thomas GJ Moncada S (2006) Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1α in cancer: role of free radical formation. Cancer Res 66, 770 774.
Quintero M, Colombo SL, Godfrey A Moncada S (2006) Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA 103, 5379 5384.
Chaplin DJ, Olive PL Durand RE (1987) Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res 47, 597 601.
Coleman CN (1988) Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity. J Natl Cancer Inst 80, 310 317.
Chaplin DJ Hill SA (1995) Temporal heterogeneity in microregional erythrocyte flux in experimental solid tumours. Br J Cancer 71, 1210 1213.
Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, Hong K Dewhirst MW (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56, 5522 5528.
Dewhirst MW (1998) Concepts of oxygen transport at the microcirculatory level. Semin Radiat Oncol 8, 143 150.
Brurberg KG, Graff BA Rofstad EK (2003) Temporal heterogeneity in oxygen tension in human melanoma xenografts. Br J Cancer 89, 350 356.
Brurberg KG, Skogmo HK, Graff BA, Olsen DR Rofstad EK (2005) Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy. Radiother Oncol 77, 220 226.
Baudelet C, Ansiaux R, Jordan BF, Havaux X, Macq B Gallez B (2004) Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia? Phys Med Biol 49, 3389 3411.
Lanzen J, Braun RD, Klitzman B, Brizel D, Secomb TW Dewhirst MW (2006) Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. Cancer Res 66, 2219 2223.
Martinive P, De Wever J, Bouzin C, Baudelet C, Sonveaux P, Gregoire V, Gallez B Feron O (2006) Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery. Mol Cancer Ther 5, 1620 1627.
Gatenby RA Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4, 891 899.
Dewhirst MW, Cao Y Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8, 425 437.
Martinive P, Defresne F, Bouzin C, Saliez J, Lair F, Gregoire V, Michiels C, Dessy C Feron O (2006) Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications for anticancer therapies. Cancer Res 66, 11736 11744.
Baudelet C Gallez B (2002) How does blood oxygen level-dependent (BOLD) contrast correlate with oxygen partial pressure (pO2) inside tumors? Magn Reson Med 48, 980 986.
Baudelet C, Cron GO, Ansiaux R, Crokart N, Dewever J, Feron O Gallez B (2006) The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*-weighted GRE signal within tumors. NMR Biomed 19, 69 76.
Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH Melillo G (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65, 9047 9055.
Brahimi-Horn C, Mazure N Pouyssegur J (2005) Signalling via the hypoxia-inducible factor-1α requires multiple posttranslational modifications. Cell Signal 17, 1 9.
Minet E, Michel G, Mottet D, Raes M Michiels C (2001) Transduction pathways involved in hypoxia-inducible factor-1 phosphorylation and activation. Free Radic Biol Med 31, 847 855.
Zhou J, Schmid T, Frank R Brune B (2004) PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1α from pVHL-independent degradation. J Biol Chem 279, 13506 13513.
Cardenas-Navia LI, Mace D, Richardson RA, Wilson DF, Shan S Dewhirst MW (2008) The pervasive presence of fluctuating oxygenation in tumors. Cancer Res 68, 5812 5819.
Brouet A, Sonveaux P, Dessy C, Balligand JL Feron O (2001) Hsp90 ensures the transition from the early Ca2 +-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells. J Biol Chem 276, 32663 32669.
Brouet A, Sonveaux P, Dessy C, Moniotte S, Balligand JL Feron O (2001) Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins. Circ Res 89, 866 873.
Powis G, Ihle N Kirkpatrick DL (2006) Practicalities of drugging the phosphatidylinositol-3-kinase/Akt cell survival signaling pathway. Clin Cancer Res, 12, 2964 2966.
Sonveaux P, Martinive P, Dewever J, Batova Z, Daneau G, Pelat M, Ghisdal P, Gregoire V, Dessy C, Balligand JL et al. (2004) Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis. Circ Res 95, 154 161.
James PE, Jackson SK, Grinberg OY Swartz HM (1995) The effects of endotoxin on oxygen consumption of various cell types in vitro: an EPR oximetry study. Free Radic Biol Med 18, 641 647.
Gallez B, Baudelet C Jordan BF (2004) Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 17, 240 262.
Jordan BF, Gregoire V, Demeure RJ, Sonveaux P, Feron O, O'Hara J, Vanhulle VP, Delzenne N Gallez B (2002) Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res 62, 3555 3561.