Abstract
We have investigated the role of HIF-1 in the cellular response to redox modulation via the inhibition of oxidative phosphorylation. We demonstrate that manipulation of redox in air, achieved by inhibiting cytochrome oxidase with cyanide, induces HIF-1 mediated transcription in wild-type CHO and HT1080 human tumour cells but not in CHO cells deficient in the oxygen responsive, HIF-1α sub-unit of HIF-1. Hypoglycaemia attenuates cyanide-mediated transcription in non-transformed HIF-1 wild-type CHO cells but not the human tumour derived cell line. Cells lacking either HIF-1α, or the second composite sub-unit of HIF-1, HIF-1β, were markedly more sensitive to the combined stress of perturbed redox and hypoglycaemia than wild-type cells. As such conditions together with hypoxia are prevalent in tumours, these data suggest that HIF-1 may have a protective role in adaptation to the tumour micro-environment. In support of this we demonstrate that HIF-1α deficient cells are less tumorigenic than wild-type cells. They showed a reduced growth rate when grown as xenografts in nude mice. This was not related to vascular parameters that were identical to those found in HIF-1 wild-type tumours. The HIF-1 deficient tumours lacked focal expression of Glut-1 in hypoxic tumour regions. Compromized glucose uptake and metabolic adaptation to the tumour micro-environment may form the basis of the reduced tumorigenecity associated with these cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Agani FH, Pichiule P, Chavez JC, La Manna JC . 2000 J. Biol Chem. 275: 35863–35867
Airley R, Loncaster J, Davidson S, Bromley M, Roberts S, Patterson A, Stratford IJ, West C . 2001 Clin. Cancer Res. 7: 928–934
Behrooz A, Ismail-Beigi F . 1997 J. Biol. Chem. 272: 5555–5562
Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL . 2000 Cancer Res. 60: 7106–7113
Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G . 2000 Cancer Res. 60: 4693–4696
Brown RS, Leung JY, Fisher SJ, Frey KA, Ethier SP, Wahl RL . 1996 J. Nucl. Med. 37: 1042–1047
Bussink J, Kaanders JHAM, Rijken PFJW, Martindale CA, van der Kogel AJ . 1998 Br. J. Cancer 77: 57–64
Carmeliet P, Dor Y, Herbert J-M, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe PJ, Moons L, Jain RK, Collen D, Keshet E . 1998 Nature 394: 485–490
Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT . 1998 Proc. Natl. Acad. Sci. USA 95: 11715–11720
Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT . 2000 J. Biol. Chem. 275: 25130–25138
Chung JK, Lee YJ, Kim C, Choi SR, Kim M, Lee K, Jeong JM, Lee DS, Jang JJ, Lee MC . 1999 J. Nucl. Med. 40: 339–446
Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KMS, Stratford IJ, Harris AL . 1997 Nature Med. 3: 515–520
Dang CV, Lewis BC, Dolde C, Dang G, Shim H . 1997 J. Bioenerget. Biomembranes 29: 345–354
Griffiths JR, McSheehy PMJ, Robinson SP, Troy H, Chung Y-L, Jackson D, Williams KJ, Stratford IJ, Stubbs M . Cancer Res. in press
Hodgkiss RJ, Jones G, Long A, Parrick J, Smith KA, Stratford MRL, Wilson GD . 1991 Br. J. Cancer 63: 119–125
Ivan M, Kondo K, Yang H, Kim W, Valiandro J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG . 2001 Science 292: 464–468
Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J., Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ . 2001 Science 292: 468–472
Jiang B-H, Agani F, Passaniti A, Semenza GL . 1997 Cancer Res. 57: 5328–5335
Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW, Ratcliffe PJ . 1991 Proc. Natl. Acad. Sci. USA 94: 8104–8109
Necas E, Thornling EB . 1972 Am. J. Physiol. 22: 1187–1190
Pugh CW, Tan CC, Jones RW, Ratcliffe PJ . 1991 Proc. Natl. Acad. Sci. USA 88: 10553–10557
Raleigh JA, Chou SC, Arteel GE, Horsman MR . 1999 Radiat. Res. 151: 580–589
Ratcliffe PJ, O'Rourke JF, Maxwell PH, Pugh CW . 1998 J. Exp. Biol. 201: 1153–1162
Ryan HE, Lo J, Johnson RS . 1998 EMBO. J. 17: 3005–3015
Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, Johnson RS . 2000 Cancer Res. 60: 4010–4015
Srinivas V, Leshchinsky I, Sang N, King M, Minchenko A, Caro J . 2001 J. Biol. Chem. 276: 21995–21998
Stratford IJ, Patterson AV, Dachs GU, Telfer B, Williams KJ . 1999 Tumour hypoxia: pathophysiology, clinical significance and therapeutic perspectives Vaupel P and Kelleher DK (eds) Wissenschaftliche verlagsgesellschaft mbh: Stuttgart pp. 107–113
Tan CC, Ratcliffe PJ . 1991 Am. J. Physiol. 261: F982–F987
Tian H, McKnight SL, Russell DW . 1997 Genes Dev. 11: 72–82
Teicher BA . 1994 Cancer Metas. Rev. 13: 139–168
Wood SM, Gleadle JM, Pugh CW, Hankinson O, Ratcliffe PJ . 1996 J. Biol. Chem. 271: 15117–15123
Wood SM, Wiesener MS, Yeates KM, Okada N, Pugh CW, Maxwell PH, Ratcliffe PJ . 1998 J. Biol. Chem. 273: 8360–8368
Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubenstein M, Cohen B . 1998 EMBO. J. 17: 5085–5094
Zhong H, Agani F, Baccala AA, Laughner E, Rioseco-Camacho N, Isaacs WB, Simons JW, Semenza GL . 1998 Cancer Res. 58: 5280–5284
Zhong H, De Marzo A, Laughner E, Lim M, Hilton DA, Zagzag D, Buecherler P, Isaacs WB, Semenza GL, Simons JW . 1999 Cancer Res. 59: 5830–5835
Acknowledgements
Thanks are due to Professor Peter Ratcliffe for supplying cell lines and for critically reviewing these studies. The collaboration with Albert van der Kogel was initiated via the Biomed II Concerted Action Programme (Development of Methods for the Rapid Analysis of Tumour Oxygenation to Allow Treatment Stratification; contract BMH4983006). This work was funded by the Medical Research Council.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Williams, K., Telfer, B., Airley, R. et al. A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis. Oncogene 21, 282–290 (2002). https://doi.org/10.1038/sj.onc.1205047
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205047
Keywords
This article is cited by
-
MiR-378a inhibits glucose metabolism by suppressing GLUT1 in prostate cancer
Oncogene (2022)
-
Gene-expression profiling of microdissected breast cancer microvasculature identifies distinct tumor vascular subtypes
Breast Cancer Research (2012)
-
Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas
BMC Cancer (2011)
-
Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy
BMC Cancer (2010)
-
Contribution of HIF-1 and drug penetrance to oxaliplatin resistance in hypoxic colorectal cancer cells
British Journal of Cancer (2009)