Skip to main content
Erschienen in: Strahlentherapie und Onkologie 4/2012

01.04.2012 | Original article

Basal HIF-1α expression levels are not predictive for radiosensitivity of human cancer cell lines

verfasst von: D. Schilling, C. Bayer, K. Emmerich, M. Molls, P. Vaupel, R.M. Huber, Prof. Dr. G. Multhoff

Erschienen in: Strahlentherapie und Onkologie | Ausgabe 4/2012

Einloggen, um Zugang zu erhalten

Abstract

Background and purpose

High levels of hypoxia inducible factor (HIF)-1α in tumors are reported to be associated with tumor progression and resistance to therapy. To examine the impact of HIF-1α on radioresistance under normoxia, the sensitivity towards irradiation was measured in human tumor cell lines that differ significantly in their basal HIF-1α levels.

Material and methods

HIF-1α levels were quantified in lysates of H1339, EPLC-272H, A549, SAS, XF354, FaDu, BHY, and CX- tumor cell lines by ELISA. Protein levels of HIF-1α, HIF-2α, carbonic anhydrase IX (CA IX), and GAPDH were assessed by Western blot analysis. Knock-down experiments were performed using HIF-1α siRNA. Clonogenic survival after irradiation was determined by the colony forming assay.

Results

According to their basal HIF-1α status, the tumor cell lines were divided into low (SAS, XF354, FaDu, A549, CX-), intermediate (EPLC-272H, BHY), and high (H1339) HIF-1α expressors. The functionality of the high basal HIF-1α expression in H1339 cells was proven by reduced CA IX expression after knocking-down HIF-1α. Linear regression analysis revealed no correlation between basal HIF-1α levels and the survival fraction at either 2 or 4 Gy in all tumor cell lines investigated.

Conclusion

Our data suggest that basal HIF-1α levels in human tumor cell lines do not predict their radiosensitivity under normoxia.
Literatur
1.
Zurück zum Zitat Aebersold DM, Burri P, Beer KT et al (2001) Expression of hypoxia-inducible factor-1a: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–2916PubMed Aebersold DM, Burri P, Beer KT et al (2001) Expression of hypoxia-inducible factor-1a: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–2916PubMed
2.
Zurück zum Zitat Akakura N, Kobayashi M, Horiuchi I et al (2001) Constitutive expression of hypoxia-inducible factor-1a renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61:6548–6554PubMed Akakura N, Kobayashi M, Horiuchi I et al (2001) Constitutive expression of hypoxia-inducible factor-1a renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61:6548–6554PubMed
3.
Zurück zum Zitat Appelhoff RJ, Tian YM, Raval RR et al (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279:38458–38465PubMedCrossRef Appelhoff RJ, Tian YM, Raval RR et al (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279:38458–38465PubMedCrossRef
4.
Zurück zum Zitat Aprelikova O, Pandolfi S, Tackett S et al (2009) Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response. Cancer Res 69:616–624PubMedCrossRef Aprelikova O, Pandolfi S, Tackett S et al (2009) Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response. Cancer Res 69:616–624PubMedCrossRef
5.
Zurück zum Zitat Berra E, Benizri E, Ginouves A et al (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 22:4082–4090PubMedCrossRef Berra E, Benizri E, Ginouves A et al (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J 22:4082–4090PubMedCrossRef
6.
Zurück zum Zitat Carmeliet P, Dor Y, Herbert JM et al (1998) Role of HIF-1a in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490PubMedCrossRef Carmeliet P, Dor Y, Herbert JM et al (1998) Role of HIF-1a in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490PubMedCrossRef
7.
Zurück zum Zitat Chan DA, Sutphin PD, Denko NC, Giaccia AJ (2002) Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. J Biol Chem 277:40112–40117PubMedCrossRef Chan DA, Sutphin PD, Denko NC, Giaccia AJ (2002) Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. J Biol Chem 277:40112–40117PubMedCrossRef
8.
Zurück zum Zitat Dang DT, Chen F, Gardner LB et al (2006) Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res 66:1684–936PubMedCrossRef Dang DT, Chen F, Gardner LB et al (2006) Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. Cancer Res 66:1684–936PubMedCrossRef
9.
Zurück zum Zitat Dellas K, Bache M, Pigorsch SU et al (2008) Prognostic impact of HIF-1alpha expression in patients with definitive radiotherapy for cervical cancer. Strahlenther Onkol 184:169–174PubMedCrossRef Dellas K, Bache M, Pigorsch SU et al (2008) Prognostic impact of HIF-1alpha expression in patients with definitive radiotherapy for cervical cancer. Strahlenther Onkol 184:169–174PubMedCrossRef
10.
Zurück zum Zitat Dewhirst MW, Cao Y, Li CY, Moeller B (2007) Exploring the role of HIF-1 in early angiogenesis and response to radiotherapy. Radiother Oncol 83:249–255PubMedCrossRef Dewhirst MW, Cao Y, Li CY, Moeller B (2007) Exploring the role of HIF-1 in early angiogenesis and response to radiotherapy. Radiother Oncol 83:249–255PubMedCrossRef
11.
Zurück zum Zitat Fu XS, Choi E, Bubley GJ, Balk SP (2005) Identification of hypoxia-inducible factor-1alpha (HIF-1alpha) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation. Prostate 63:215–221PubMedCrossRef Fu XS, Choi E, Bubley GJ, Balk SP (2005) Identification of hypoxia-inducible factor-1alpha (HIF-1alpha) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation. Prostate 63:215–221PubMedCrossRef
12.
Zurück zum Zitat Greijer AE, Wall E van der (2004) The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 57:1009–1014PubMedCrossRef Greijer AE, Wall E van der (2004) The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 57:1009–1014PubMedCrossRef
13.
Zurück zum Zitat Jung SY, Song HS, Park SY (2011) Pyruvate promotes tumor angiogenesis through HIF-1-dependent PAI-1 expression. Int J Oncol 38:571–576PubMed Jung SY, Song HS, Park SY (2011) Pyruvate promotes tumor angiogenesis through HIF-1-dependent PAI-1 expression. Int J Oncol 38:571–576PubMed
14.
Zurück zum Zitat Kappler M, Taubert H, Holzhausen HJ et al (2008) Immunohistochemical detection of HIF-1a and CAIX in advanced head-and-neck cancer. Prognostic role and correlation with tumor markers and tumor oxygenation parameters. Strahlenther Onkol 184:393–399PubMedCrossRef Kappler M, Taubert H, Holzhausen HJ et al (2008) Immunohistochemical detection of HIF-1a and CAIX in advanced head-and-neck cancer. Prognostic role and correlation with tumor markers and tumor oxygenation parameters. Strahlenther Onkol 184:393–399PubMedCrossRef
15.
Zurück zum Zitat Kessler J, Hahnel A, Wichmann H et al (2010) HIF-1a inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer 10:605PubMedCrossRef Kessler J, Hahnel A, Wichmann H et al (2010) HIF-1a inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer 10:605PubMedCrossRef
16.
Zurück zum Zitat Kim WY, Oh SH, Woo JK et al (2009) Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1a. Cancer Res 69:1624–1632PubMedCrossRef Kim WY, Oh SH, Woo JK et al (2009) Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1a. Cancer Res 69:1624–1632PubMedCrossRef
17.
Zurück zum Zitat Koukourakis MI, Giatromanolaki A, Sivridis E et al (2002) Hypoxia-inducible factor (HIF1 α and HIF2 α), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53:1192–202PubMedCrossRef Koukourakis MI, Giatromanolaki A, Sivridis E et al (2002) Hypoxia-inducible factor (HIF1 α and HIF2 α), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53:1192–202PubMedCrossRef
18.
Zurück zum Zitat Krieg M, Haas R, Brauch H et al (2000) Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19:5435–5443PubMedCrossRef Krieg M, Haas R, Brauch H et al (2000) Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19:5435–5443PubMedCrossRef
19.
Zurück zum Zitat Liu J, Zhang J, Wang X et al (2010) HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res 316:1985–1993PubMedCrossRef Liu J, Zhang J, Wang X et al (2010) HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res 316:1985–1993PubMedCrossRef
20.
Zurück zum Zitat Maftei CA, Bayer C, Shi K et al (2011) Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques. Strahlenther Onkol 187:260–266PubMedCrossRef Maftei CA, Bayer C, Shi K et al (2011) Quantitative assessment of hypoxia subtypes in microcirculatory supply units of malignant tumors using (immuno-)fluorescence techniques. Strahlenther Onkol 187:260–266PubMedCrossRef
21.
Zurück zum Zitat Moeller BJ, Dreher MR, Rabbani ZN et al (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110PubMedCrossRef Moeller BJ, Dreher MR, Rabbani ZN et al (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110PubMedCrossRef
22.
Zurück zum Zitat Multhoff G, Botzler C, Jennen L et al (1997) Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 158:4341–4350PubMed Multhoff G, Botzler C, Jennen L et al (1997) Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 158:4341–4350PubMed
23.
Zurück zum Zitat Nordsmark M, Eriksen JG, Gebski V et al (2007) Differential risk assessments from five hypoxia specific assays: The basis for biologically adapted individualized radiotherapy in advanced head and neck cancer patients. Radiother Oncol 83:389–397PubMedCrossRef Nordsmark M, Eriksen JG, Gebski V et al (2007) Differential risk assessments from five hypoxia specific assays: The basis for biologically adapted individualized radiotherapy in advanced head and neck cancer patients. Radiother Oncol 83:389–397PubMedCrossRef
24.
Zurück zum Zitat Paltoglou SM, Roberts BJ (2005) Role of the von Hippel-Lindau tumour suppressor protein in the regulation of HIF-1alpha and its oxygen-regulated transactivation domains at high cell density. Oncogene 24:3830–3835PubMedCrossRef Paltoglou SM, Roberts BJ (2005) Role of the von Hippel-Lindau tumour suppressor protein in the regulation of HIF-1alpha and its oxygen-regulated transactivation domains at high cell density. Oncogene 24:3830–3835PubMedCrossRef
25.
Zurück zum Zitat Sasabe E, Tatemoto Y, Li D et al (2005) Mechanism of HIF-1a-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells. Cancer Sci 96:394–402PubMedCrossRef Sasabe E, Tatemoto Y, Li D et al (2005) Mechanism of HIF-1a-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells. Cancer Sci 96:394–402PubMedCrossRef
26.
Zurück zum Zitat Schilling D, Gehrmann M, Steinem C et al (2009) Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J 23:2467–2477PubMedCrossRef Schilling D, Gehrmann M, Steinem C et al (2009) Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J 23:2467–2477PubMedCrossRef
28.
Zurück zum Zitat Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634PubMedCrossRef Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634PubMedCrossRef
29.
Zurück zum Zitat Staab A, Fleischer M, Loeffler J et al (2011) Small interfering RNA targeting HIF-1a reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro. Strahlenther Onkol 187:252–259PubMedCrossRef Staab A, Fleischer M, Loeffler J et al (2011) Small interfering RNA targeting HIF-1a reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro. Strahlenther Onkol 187:252–259PubMedCrossRef
30.
Zurück zum Zitat Strofer M, Jelkmann W, Depping R (2011) Curcumin decreases survival of Hep3B liver and MCF-7 breast cancer cells: the role of HIF. Strahlenther Onkol 187:393–400PubMedCrossRef Strofer M, Jelkmann W, Depping R (2011) Curcumin decreases survival of Hep3B liver and MCF-7 breast cancer cells: the role of HIF. Strahlenther Onkol 187:393–400PubMedCrossRef
31.
Zurück zum Zitat Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRef Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRef
32.
Zurück zum Zitat Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354PubMedCrossRef Vaupel P, Mayer A, Höckel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354PubMedCrossRef
33.
Zurück zum Zitat Zips D, Boke S, Kroeber T et al (2011) Prognostic value of radiobiological hypoxia during fractionated irradiation for local tumor control. Strahlenther Onkol 187:306–310PubMedCrossRef Zips D, Boke S, Kroeber T et al (2011) Prognostic value of radiobiological hypoxia during fractionated irradiation for local tumor control. Strahlenther Onkol 187:306–310PubMedCrossRef
Metadaten
Titel
Basal HIF-1α expression levels are not predictive for radiosensitivity of human cancer cell lines
verfasst von
D. Schilling
C. Bayer
K. Emmerich
M. Molls
P. Vaupel
R.M. Huber
Prof. Dr. G. Multhoff
Publikationsdatum
01.04.2012
Verlag
Springer-Verlag
Erschienen in
Strahlentherapie und Onkologie / Ausgabe 4/2012
Print ISSN: 0179-7158
Elektronische ISSN: 1439-099X
DOI
https://doi.org/10.1007/s00066-011-0051-6

Weitere Artikel der Ausgabe 4/2012

Strahlentherapie und Onkologie 4/2012 Zur Ausgabe

Mitteilungen der Fachgesellschaften

Mitteilungen

15% bedauern gewählte Blasenkrebs-Therapie

29.05.2024 Urothelkarzinom Nachrichten

Ob Patienten und Patientinnen mit neu diagnostiziertem Blasenkrebs ein Jahr später Bedauern über die Therapieentscheidung empfinden, wird einer Studie aus England zufolge von der Radikalität und dem Erfolg des Eingriffs beeinflusst.

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

28.05.2024 Nebenwirkungen der Krebstherapie Nachrichten

Kardiotoxische Nebenwirkungen einer Therapie mit Immuncheckpointhemmern mögen selten sein – wenn sie aber auftreten, wird es für Patienten oft lebensgefährlich. Voruntersuchung und Monitoring sind daher obligat.

Costims – das nächste heiße Ding in der Krebstherapie?

28.05.2024 Onkologische Immuntherapie Nachrichten

„Kalte“ Tumoren werden heiß – CD28-kostimulatorische Antikörper sollen dies ermöglichen. Am besten könnten diese in Kombination mit BiTEs und Checkpointhemmern wirken. Erste klinische Studien laufen bereits.

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

28.05.2024 NSCLC Nachrichten

Eine perioperative Therapie mit Nivolumab reduziert das Risiko für Rezidive und Todesfälle bei operablem NSCLC im Vergleich zu einer alleinigen neoadjuvanten Chemotherapie um über 40%. Darauf deuten die Resultate der Phase-3-Studie CheckMate 77T.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.