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Journal of Cancer Research and Clinical Oncology

Published in:

01-10-2015 | Original Article – Cancer Research

Paraoxonase-2 (PON2) protects oral squamous cell cancer cells against irradiation-induced apoptosis

Authors: Maximilian Krüger, Andreas Max Pabst, Bilal Al-Nawas, Sven Horke, Maximilian Moergel

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2015

Abstract

Purpose

Patients with oral squamous cell carcinomas (OSCC) often receive radiotherapy to preferentially induce apoptosis of cancer cells through generation of overwhelming DNA damage. This is amplified by generation of reactive oxygen species (ROS), thereby causing oxidative stress and cell death. However, tumors resist through different mechanisms, including upregulation of anti-apoptotic factors and enhanced ROS resistance. We recently reported that the antioxidative enzyme PON2 significantly enhances cellular stress resistance by attenuating mitochondrial ROS-mediated apoptosis. Further, PON2 is often upregulated in cancer. This prompted us to investigate its yet unknown role in the protection of OSCC against irradiation-induced cell death.

Methods

PON2 expression was determined after 7 Gy singular irradiation in four OSCC cell lines (PCI-13, PCI-52, SCC-4, SCC-68) accompanied by the detection of caspase 3/7 activity. A direct role of PON2 was tested by siRNA-mediated knockdown. In vivo PON2 expression was tested in five patients with oral carcinoma and compared with healthy mucosa for the evaluation of clinical significance.

Results

PON2 is variably expressed in OSCC in vitro and in vivo. Compared with the other cell lines, SCC-4 cells showed twofold more basal PON2 (p ≤ 0.05) and the lowest caspase 3/7 activity after singular irradiation (p ≤ 0.05). Contrarily, irradiation led to 1.2-fold induction of PON2 in PCI-13 with no effect on SCC-4 (≤0.05), suggesting that PON2 levels reflect the cells’ irradiation sensitivity. In agreement, PON2 knockdown resulted in significant higher apoptosis rates (p ≤ 0.05).

Conclusion

Our findings give first evidence that upregulation of PON2 may protect OSCC against irradiation-induced apoptosis.

Adam-Vizi V, Chinopoulos C (2006) Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 27:639–645. doi:10.1016/j.tips.2006.10.005 CrossRefPubMed

Altenhofer S et al (2010) One enzyme, two functions: PON2 prevents mitochondrial superoxide formation and apoptosis independent from its lactonase activity. J Biol Chem 285:24398–24403. doi:10.1074/jbc.M110.118604 PubMedCentralCrossRefPubMed

Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN (1998) Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Investig 101:1581–1590. doi:10.1172/JCI1649 PubMedCentralCrossRefPubMed

Benhar M, Dalyot I, Engelberg D, Levitzki A (2001) Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 21:6913–6926. doi:10.1128/MCB.21.20.6913-6926.2001 PubMedCentralCrossRefPubMed

Bourhis J et al (2006) Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 368:843–854. doi:10.1016/S0140-6736(06)69121-6 CrossRefPubMed

Camps J, Marsillach J, Joven J (2009) The paraoxonases: role in human diseases and methodological difficulties in measurement. Crit Rev Clin Lab Sci 46:83–106. doi:10.1080/10408360802610878 CrossRefPubMed

Chandra D, Singh KK (2011) Genetic insights into OXPHOS defect and its role in cancer. Biochim Biophys Acta 1807:620–625. doi:10.1016/j.bbabio.2010.10.023 CrossRefPubMed

Chen Y et al (2012) Association analysis of PON polymorphisms in sporadic ALS in a Chinese population. Neurobiol Aging 33(2949):e2941–e2943. doi:10.1016/j.neurobiolaging.2012.06.024

Citak E, Tulek Z (2013) Longitudinal quality of life in Turkish patients with head and neck cancer undergoing radiotherapy. Support Care Cancer 21:2171–2183. doi:10.1007/s00520-013-1774-y CrossRefPubMed

Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J17:1195–1214. doi:10.1096/fj.02-0752rev CrossRef

Decaudin D, Marzo I, Brenner C, Kroemer G (1998) Mitochondria in chemotherapy-induced apoptosis: a prospective novel target of cancer therapy (review). Int J Oncol 12:141–152PubMed

Devarajan A et al (2011) Paraoxonase 2 deficiency alters mitochondrial function and exacerbates the development of atherosclerosis. Antioxid Redox Signal 14:341–351. doi:10.1089/ars.2010.3430 PubMedCentralCrossRefPubMed

Ding ZY, Liu GH, Olsson B, Sun XF (2012) Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells. Tumour Biol. doi:10.1007/s13277-012-0596-8

Draganov DI, Stetson PL, Watson CE, Billecke SS, La Du BN (2000) Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J Biol Chem 275:33435–33442. doi:10.1074/jbc.M004543200 CrossRefPubMed

Eckert AW, Kappler M, Schubert J, Taubert H (2012) Correlation of expression of hypoxia-related proteins with prognosis in oral squamous cell carcinoma patients. Oral Maxillofac Surg 16:189–196. doi:10.1007/s10006-012-0335-8 CrossRefPubMed

Eriksson D, Stigbrand T (2010) Radiation-induced cell death mechanisms. Tumour Biol 31:363–372. doi:10.1007/s13277-010-0042-8 CrossRefPubMed

Fang J, Nakamura H, Iyer AK (2007) Tumor-targeted induction of oxystress for cancer therapy. J Drug Target 15:475–486. doi:10.1080/10611860701498286 CrossRefPubMed

Fiaschi AI, Cozzolino A, Ruggiero G, Giorgi G (2005) Glutathione, ascorbic acid and antioxidant enzymes in the tumor tissue and blood of patients with oral squamous cell carcinoma. Eur Rev Med Pharmacol Sci 9:361–367PubMed

Frank O et al (2006) Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients. Leukemia 20:1400–1407. doi:10.1038/sj.leu.2404270 CrossRefPubMed

Fribley AM et al (2014) Celastrol induces unfolded protein response-dependent cell death in head and neck cancer. Exp Cell Res. doi:10.1016/j.yexcr.2014.08.014 PubMedCentralPubMed

Fruehauf JP, Meyskens FL Jr (2007) Reactive oxygen species: a breath of life or death? Clin Cancer Res 13:789–794. doi:10.1158/1078-0432.CCR-06-2082 CrossRefPubMed

Gasco M, Crook T (2003) The p53 network in head and neck cancer. Oral Oncol 39:222–231CrossRefPubMed

Hashibe M et al (2003) Meta- and pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer. Cancer Epidemiol Biomark Prev 12:1509–1517

Horke S, Witte I, Wilgenbus P, Kruger M, Strand D, Forstermann U (2007) Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation. Circulation 115:2055–2064. doi:10.1161/CIRCULATIONAHA.106.681700 CrossRefPubMed

Horke S, Witte I, Wilgenbus P, Altenhofer S, Kruger M, Li H, Forstermann U (2008) Protective effect of paraoxonase-2 against endoplasmic reticulum stress-induced apoptosis is lost upon disturbance of calcium homoeostasis. Biochem J416:395–405. doi:10.1042/BJ20080775 CrossRef

Horke S et al (2010) Paraoxonase 2 is down-regulated by the Pseudomonas aeruginosa quorumsensing signal N-(3-oxododecanoyl)-l-homoserine lactone and attenuates oxidative stress induced by pyocyanin. Biochem J426:73–83. doi:10.1042/BJ20091414 CrossRef

Jerhammar F et al (2014) YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Oral Oncol. doi:10.1016/j.oraloncology.2014.06.003 PubMed

Jonathan EC, Bernhard EJ, McKenna WG (1999) How does radiation kill cells? Curr Opin Chem Biol 3:77–83CrossRefPubMed

Kang H et al (2010) Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood 115:1394–1405. doi:10.1182/blood-2009-05-218560 PubMedCentralCrossRefPubMed

Khersonsky O, Tawfik DS (2005) Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase. Biochemistry 44:6371–6382. doi:10.1021/bi047440d CrossRefPubMed

Kishimoto K, Yoshida S, Ibaragi S, Yoshioka N, Okui T, Hu GF, Sasaki A (2012) Hypoxia-induced up-regulation of angiogenin, besides VEGF, is related to progression of oral cancer. Oral Oncol 48:1120–1127. doi:10.1016/j.oraloncology.2012.05.009 CrossRefPubMed

Korde SD, Basak A, Chaudhary M, Goyal M, Vagga A (2011) Enhanced nitrosative and oxidative stress with decreased total antioxidant capacity in patients with oral precancer and oral squamous cell carcinoma. Oncology 80:382–389. doi:10.1159/000329811 CrossRefPubMed

Kutler DI et al (2003) High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg 129:106–112CrossRefPubMed

La Vecchia C, Lucchini F, Negri E, Levi F (2004) Trends in oral cancer mortality in Europe. Oral Oncol 40:433–439. doi:10.1016/j.oraloncology.2003.09.013 CrossRefPubMed

Lacko M et al (2014) Genetic susceptibility to head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 89:38–48. doi:10.1016/j.ijrobp.2013.09.034 CrossRefPubMed

Li Y et al (2002) Discovery and analysis of hepatocellular carcinoma genes using cDNA microarrays. J Cancer Res Clin Oncol 128:369–379. doi:10.1007/s00432-002-0347-0 CrossRefPubMed

Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977. doi:10.1038/nrc1505 CrossRefPubMed

Malik UU, Siddiqui IA, Hashim Z, Zarina S (2014) Measurement of serum paraoxonase activity and MDA concentrations in patients suffering with oral squamous cell carcinoma. Clin Chim Acta 430C:38–42. doi:10.1016/j.cca.2013.12.033 CrossRef

Marsillach J, Mackness B, Mackness M, Riu F, Beltran R, Joven J, Camps J (2008) Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Radic Biol Med 45:146–157. doi:10.1016/j.freeradbiomed.2008.03.023 CrossRefPubMed

Massano J, Regateiro FS, Januario G, Ferreira A (2006) Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:67–76. doi:10.1016/j.tripleo.2005.07.038 CrossRefPubMed

Moergel M, Goldschmitt J, Stockinger M, Kunkel M (2013) DeltaNp63 expression in four carcinoma cell lines and the effect on radioresistance-a siRNA knockdown model. Clin Oral Investig. doi:10.1007/s00784-013-1078-0

Ocker M, Hopfner M (2012) Apoptosis-modulating drugs for improved cancer therapy. Eur Surg Res 48:111–120. doi:10.1159/000336875 CrossRefPubMed

Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922. doi:10.1007/s10495-007-0756-2 CrossRefPubMed

Panganiban RA, Mungunsukh O, Day RM (2013) X-irradiation induces ER stress, apoptosis, and senescence in pulmonary artery endothelial cells. Int J Radiat Biol 89:656–667. doi:10.3109/09553002.2012.711502 CrossRefPubMed

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMed

Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN (1996) The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 33:498–507CrossRefPubMed

Rasheed MH, Beevi SS, Geetha A (2007) Enhanced lipid peroxidation and nitric oxide products with deranged antioxidant status in patients with head and neck squamous cell carcinoma. Oral Oncol 43:333–338. doi:10.1016/j.oraloncology.2006.02.013 CrossRefPubMed

Rathod S, Gupta T, Ghosh-Laskar S, Murthy V, Budrukkar A, Agarwal J (2013) Quality-of-life (QOL) outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT) compared to three-dimensional conformal radiotherapy (3D-CRT): evidence from a prospective randomized study. Oral Oncol 49:634–642. doi:10.1016/j.oraloncology.2013.02.013 CrossRefPubMed

Ribarska T, Ingenwerth M, Goering W, Engers R, Schulz WA (2010) Epigenetic inactivation of the placentally imprinted tumor suppressor gene TFPI2 in prostate carcinoma. Cancer Genomics Proteomics 7:51–60PubMed

Ricci MS, Zong WX (2006) Chemotherapeutic approaches for targeting cell death pathways. Oncologist 11:342–357. doi:10.1634/theoncologist.11-4-342 PubMedCentralCrossRefPubMed

Ross ME et al (2003) Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 102:2951–2959. doi:10.1182/blood-2003-01-0338 CrossRefPubMed

Rothenberg SM, Ellisen LW (2012) The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Investig 122:1951–1957PubMedCentralCrossRefPubMed

Schafer ZT et al (2009) Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461:109–113. doi:10.1038/nature08268 PubMedCentralCrossRefPubMed

Schweikert EM et al (2012) PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death. Cell Death Differ. doi:10.1038/cdd.2012.35 PubMedCentralPubMed

Shih DM, Lusis AJ (2009) The roles of PON1 and PON2 in cardiovascular disease and innate immunity. Curr Opin Lipidol 20:288–292. doi:10.1097/MOL.0b013e32832ca1ee CrossRefPubMed

Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, LLeonart ME (2013) Oxidative stress and cancer: an overview. Ageing Res Rev 12:376–390. doi:10.1016/j.arr.2012.10.004 CrossRefPubMed

Srivastava KC, Austin RD, Shrivastava D, Sethupathy S, Rajesh S (2012) A Case control study to evaluate oxidative stress in plasma samples of oral malignancy. Contemp Clin Dent 3:271–276. doi:10.4103/0976-237X.103617 PubMedCentralCrossRefPubMed

Stevens EA, Rodriguez CP (2014) Genomic medicine and targeted therapy for solid tumors. J Surg Oncol. doi:10.1002/jso.23699 PubMed

Suh DH, Kim MK, Kim HS, Chung HH, Song YS (2012) Unfolded protein response to autophagy as a promising druggable target for anticancer therapy. Ann NY Acad Sci 1271:20–32. doi:10.1111/j.1749-6632.2012.06739.x PubMedCentralCrossRefPubMed

Suntharalingam M et al (2001) Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck. Cancer 91:548–554CrossRefPubMed

Trotti A et al (2003) Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 66:253–262CrossRefPubMed

Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40. doi:10.1016/j.cbi.2005.12.009 CrossRefPubMed

Vaseva AV, Moll UM (2009) The mitochondrial p53 pathway. Biochim Biophys Acta 1787:414–420. doi:10.1016/j.bbabio.2008.10.005 PubMedCentralCrossRefPubMed

Vaughn AE, Deshmukh M (2008) Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol 10:1477–1483. doi:10.1038/ncb1807 PubMedCentralCrossRefPubMed

Wang D, Kreutzer DA, Essigmann JM (1998) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat Res 400:99–115CrossRefPubMed

Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J313(Pt 1):17–29CrossRef

Witte I et al (2011) Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells. Cell Death Dis 2:e112. doi:10.1038/cddis.2010.91 PubMedCentralCrossRefPubMed

Title: Paraoxonase-2 (PON2) protects oral squamous cell cancer cells against irradiation-induced apoptosis
Authors: Maximilian Krüger
Andreas Max Pabst
Bilal Al-Nawas
Sven Horke
Maximilian Moergel
Publication date: 01-10-2015
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 10/2015
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-1941-2

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