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Year 2015, Volume: 42 Issue: 3, 361 - 367, 24.10.2015

Nedim Karagenç , Duygu Meydancı Hakan Küçüksayan

https://doi.org/10.5798/diclemedj.0921.2015.03.0590

Abstract

Objective: In this study, it was aimed to investigate that PON2, in hypoxia and normoxia in relation to HIF-1α transcription factor that has a role in tumour angiogenesis. Hypoxia inducible factor 1 alpha (HIF-1α) is a transcription factor which is sensitive to hypoxia, causes initiation of angiogenesis and metastasis by providing transcription of numerous genes. As well as hypoxia several inflammatory agents such as lipopolysaccharide (LPS) can regulate the expression of HIF-1α as well as PON2. Oxidative stress is known to have role in cancer. Paraoxonase 2 which is one of the members of paraoxonase family serves as intracellular anti-oxidant. Methods: H1299, A549 ve PC14 non-small cell lung carcinoma cell lines used in this study. Cells were cultured under hypoxia and normoxia conditions with LPS stimulation. HIF-1α and PON2 mRNA expression levels measured by real-time PCR. Western blot studies were performed for protein expression.Results: In this study, it was observed that LPS treatment stimulates HIF-1α expression which increases PON2 expression in NSCLC cell line in under hxpoxia conditions. Conclusion: This study shows that PON2 is regulated by HIF-1α in hypoxia and inflammation. The relationship between hypoxia and inflammation and oxidative status of cells requires further studies

Keywords

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References

  • Lou JJ, Chua YL, Chew EH, et al. Inhibition of hypoxiainducible
  • factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. PLoS One 2010;5: e10522.
  • Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev 2001;11:293-299.
  • Kim J-W Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.Cell Metab 2006;3:177-185.
  • Tracy K, Dibling BC, Spike BT, et al. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 2007;27:6229-6242.
  • Liu L, Ning X, Sun L, Zhang H, et al. Hypoxia-inducible factor-1α contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci 2008;99:121-128.
  • Airley RE, Mobasheri A. Hypoxic regulation of glucose transport, anaerobic metabolism and angiogenesis in cancer:novel pathways and targets for anticancer therapeutics. Chemotherapy 2007;53:233-256.
  • Metzen E, Zhou J, Jelkmann W, et al. Nitric oxide impairs
  • normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases.
  • Mol Biol Cell 2003;14:3470-3481.
  • El Awad B, Kreft B, Wolber EM, et al. Hypoxia and interleukin-1β stimulate vascular endothelial growth factor production in human proximal tubular cells. Kidney Int 2000;58:43-50.
  • Peyssonaux C, Johnson RS. An unexpected role for hypoxic response: oxygenation and inflammation. Cell Cycle 2004;3:168-171.
  • Sang N, Stiehl DP, Bohensky J, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 2003;278:14013-14019.
  • Van der Bruggen T, Nijenhuis S, van Raaij E, Verhoef J, Sweder van Asbeck, B. Lipopolysaccharide-induced tumor necrosis factor α roduction by human monocytes involves the Raf-1/MEK1-EK2/ERK1-ERK2 pathway. Infect Immun 1999;67, 3824-3829.
  • Agani FHP, Pichiule JC, Chavez, LaManna JC. The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem 2000:275:35863-35867.
  • Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2
  • sensing. J Biol Chem 2000:275:25130-25138.
  • Guzy RD, Hoyos B, Robin E, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 2005;1:401-408.
  • Callapina M, Zhou J, Schmid T, Kohl R, Brune B. NO restores
  • HIF-1- hydroxylation during hypoxia: role of reactive oxygen species. Free Radic Biol Med 2005;39:925-936.
  • Wartenberg MF, Ling C, Muschen M, et al. Regulation of the
  • multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB J 2003:17:503–505.
  • Ng CJ, Wadleigh DJ, Gangopadhyay A, et al. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 2001;276:44444-44449.
  • Çevik M.U, Varol S, Yücel Y, ve ark. Serum paraoxonase-1 activities and malondialdehyde levels in patients with epilepsy.
  • Dicle Med J 2012;3:557-560.
  • Çavdaroğlu B, Köse N, Başkol G, Demir H. Evaluation of protein and lipid oxidative stress in the patients with postmenopausal osteoporosis. Dicle Med J 2014;41:71-77.
  • Elkıran ET, Mar N, Aygen B, et al. Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population. BMC Cancer 2007;7:48.
  • Lee CH, Lee KY, Choe KH, et al. Effects of oxidative DNA damage induced by polycyclic aromatic hydrocarbons and genetic polymorphism of the paraoxonase-1 (PON1) gene on lung cancer. J Prev Med Pub Health 2005;38:345-350.
  • Shih DM, Gu L, Hama S, et al. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest 1996;97:1630-1639.
  • Rosenblat M, Draganov D, Watson CE, et al. Mouse macrophage
  • paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol 2003;23:468-474.
  • Precourt LP, Seidman E, Delvin E, et al. Comparative expression analysis reveals differences in the regulation of intestinal paraoxonase family members. Int J Biochem Cell Biol 2009;41:1628-1637.
  • Frede S, Stockmann C, Freitag P, Fandery J. Bacterial ipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB. Biochem J 2006;396:517–527.
  • Blouin CC, Page EL, Soucy GM, Richard DE. Hypoxic gene
  • activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α. Blood 2004;103:1124-1130.
  • Li Q F, Wang XR, Yang J, Lin H. Hypoxia upregulates hypoxia
  • inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α. Cell Research 2006;16:548-558.
  • Poitz DM, Augstein A, Hesse K, et al. Regulation of the HIF-system in human macrophages – Differential regulation of HIF-α subunits under sustained hypoxia. Molecul Immunol 2014;57:226–235.
  • Behn C, Araneda OF, Llanos AJ, et al. Hypoxia-related lipid peroxidation: evidences, implications and approaches. Respir Physiol Neurobiol 2007;30;158:143-150.
  • Ji LL, Gómez-Cabrera MC, Vina J. Exercise and hormesis: activation of cellular antioxidant signaling pathway Ann.
  • N.Y. Acad. Sci 2006;1067:425–435.
  • Feingold KR, Memon RA , Moser AH, Grunfeld C. Paraoxonase
  • activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 1998;139:307–315.
  • Dumitru CD, Ceci JD, Tsatsanis C, et al. TNF-alpha induction
  • by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 2000;22;103:1071-1083.
  • Gao XJ, Guo MY, Zhang ZC, et al. Bergenin Plays an AntiInflammatory Role via the Modulation of MAPK and NF-κB Signaling Pathways in a Mouse Model of LPS-Induced Mastitis. Inflammation 2015;38:1142-1150.

Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması

Year 2015, Volume: 42 Issue: 3, 361 - 367, 24.10.2015

Nedim Karagenç , Duygu Meydancı Hakan Küçüksayan

https://doi.org/10.5798/diclemedj.0921.2015.03.0590

Abstract

Giriş: Bu çalışmada tümör anjiyogenezinde önemli rol oynayan hipoksi indüklenebilir faktör 1 (HIF-1) transkripsiyon faktörünün hipoksik ve normoksik koşullarda paraoksonaz 2 (PON2) ile ilişkisinin araştırılması hedeflenmiştir. Hipoksiye duyarlı bir transkripsiyon faktör olan HIF-1α çok sayıda genin transkripsiyonunu sağlayarak anjiyogenez ve metastazın başlamasına yol açar. Hipoksinin yanı sıra lipopolisakkarit (LPS) gibi çeşitli inflamatuvar ajanlar da HIF-1 α’nın ve PON2 nin ekspresyonunu düzenleyebilirler. Oksidatif stres karsinogenezde önemli etiyolojik faktörlerden birisidir. Paraoksonaz ailesi üyelerinden paraoksonaz 2 (PON2) nin hücre içi antioksidan olarak görev yaptığı bilinmektedir.

Yöntemler: H1299, A549 ve PC14 akciğer hücre dizileri normoksi ve hipoksi ortamlarında kültürü yapılarak ve lipopolisakkaritle indüklenerek HIF-1 ve PON2 mRNA ekspresyonları ve western blot tayinleri çalışılmıştır.

Bulgular: Çalışma sonucunda LPS uygulamasının HIF-1α ekspresyonunu uyardığı ve hipoksi koşullarında akciğer hücre dizilerinde PON2 ekspresyonunun arttığı gözlendi.

Sonuç: Bu çalışmada PON 2 enzim ekspresyonunun HIF-1α aracılığıyla hipoksi ve normoksi koşullarında regüle edildiği gözlenmiş olup hipoksi, inflamasyon ve hücrenin oksidatif durumu arasındaki ilişkinin aydınlatılması için ileri çalışmalar gerekebilir.

Anahtar kelimeler: HIF-1α, PON2, LPS, Hipoksi

Keywords

HIF-1α PON2 LPS Hipoksi

References

  • Lou JJ, Chua YL, Chew EH, et al. Inhibition of hypoxiainducible
  • factor-1alpha (HIF-1alpha) protein synthesis by DNA damage inducing agents. PLoS One 2010;5: e10522.
  • Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev 2001;11:293-299.
  • Kim J-W Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.Cell Metab 2006;3:177-185.
  • Tracy K, Dibling BC, Spike BT, et al. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 2007;27:6229-6242.
  • Liu L, Ning X, Sun L, Zhang H, et al. Hypoxia-inducible factor-1α contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci 2008;99:121-128.
  • Airley RE, Mobasheri A. Hypoxic regulation of glucose transport, anaerobic metabolism and angiogenesis in cancer:novel pathways and targets for anticancer therapeutics. Chemotherapy 2007;53:233-256.
  • Metzen E, Zhou J, Jelkmann W, et al. Nitric oxide impairs
  • normoxic degradation of HIF-1α by inhibition of prolyl hydroxylases.
  • Mol Biol Cell 2003;14:3470-3481.
  • El Awad B, Kreft B, Wolber EM, et al. Hypoxia and interleukin-1β stimulate vascular endothelial growth factor production in human proximal tubular cells. Kidney Int 2000;58:43-50.
  • Peyssonaux C, Johnson RS. An unexpected role for hypoxic response: oxygenation and inflammation. Cell Cycle 2004;3:168-171.
  • Sang N, Stiehl DP, Bohensky J, Caro J. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 2003;278:14013-14019.
  • Van der Bruggen T, Nijenhuis S, van Raaij E, Verhoef J, Sweder van Asbeck, B. Lipopolysaccharide-induced tumor necrosis factor α roduction by human monocytes involves the Raf-1/MEK1-EK2/ERK1-ERK2 pathway. Infect Immun 1999;67, 3824-3829.
  • Agani FHP, Pichiule JC, Chavez, LaManna JC. The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem 2000:275:35863-35867.
  • Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2
  • sensing. J Biol Chem 2000:275:25130-25138.
  • Guzy RD, Hoyos B, Robin E, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 2005;1:401-408.
  • Callapina M, Zhou J, Schmid T, Kohl R, Brune B. NO restores
  • HIF-1- hydroxylation during hypoxia: role of reactive oxygen species. Free Radic Biol Med 2005;39:925-936.
  • Wartenberg MF, Ling C, Muschen M, et al. Regulation of the
  • multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB J 2003:17:503–505.
  • Ng CJ, Wadleigh DJ, Gangopadhyay A, et al. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 2001;276:44444-44449.
  • Çevik M.U, Varol S, Yücel Y, ve ark. Serum paraoxonase-1 activities and malondialdehyde levels in patients with epilepsy.
  • Dicle Med J 2012;3:557-560.
  • Çavdaroğlu B, Köse N, Başkol G, Demir H. Evaluation of protein and lipid oxidative stress in the patients with postmenopausal osteoporosis. Dicle Med J 2014;41:71-77.
  • Elkıran ET, Mar N, Aygen B, et al. Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population. BMC Cancer 2007;7:48.
  • Lee CH, Lee KY, Choe KH, et al. Effects of oxidative DNA damage induced by polycyclic aromatic hydrocarbons and genetic polymorphism of the paraoxonase-1 (PON1) gene on lung cancer. J Prev Med Pub Health 2005;38:345-350.
  • Shih DM, Gu L, Hama S, et al. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest 1996;97:1630-1639.
  • Rosenblat M, Draganov D, Watson CE, et al. Mouse macrophage
  • paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol 2003;23:468-474.
  • Precourt LP, Seidman E, Delvin E, et al. Comparative expression analysis reveals differences in the regulation of intestinal paraoxonase family members. Int J Biochem Cell Biol 2009;41:1628-1637.
  • Frede S, Stockmann C, Freitag P, Fandery J. Bacterial ipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB. Biochem J 2006;396:517–527.
  • Blouin CC, Page EL, Soucy GM, Richard DE. Hypoxic gene
  • activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α. Blood 2004;103:1124-1130.
  • Li Q F, Wang XR, Yang J, Lin H. Hypoxia upregulates hypoxia
  • inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α. Cell Research 2006;16:548-558.
  • Poitz DM, Augstein A, Hesse K, et al. Regulation of the HIF-system in human macrophages – Differential regulation of HIF-α subunits under sustained hypoxia. Molecul Immunol 2014;57:226–235.
  • Behn C, Araneda OF, Llanos AJ, et al. Hypoxia-related lipid peroxidation: evidences, implications and approaches. Respir Physiol Neurobiol 2007;30;158:143-150.
  • Ji LL, Gómez-Cabrera MC, Vina J. Exercise and hormesis: activation of cellular antioxidant signaling pathway Ann.
  • N.Y. Acad. Sci 2006;1067:425–435.
  • Feingold KR, Memon RA , Moser AH, Grunfeld C. Paraoxonase
  • activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 1998;139:307–315.
  • Dumitru CD, Ceci JD, Tsatsanis C, et al. TNF-alpha induction
  • by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 2000;22;103:1071-1083.
  • Gao XJ, Guo MY, Zhang ZC, et al. Bergenin Plays an AntiInflammatory Role via the Modulation of MAPK and NF-κB Signaling Pathways in a Mouse Model of LPS-Induced Mastitis. Inflammation 2015;38:1142-1150.
There are 46 citations in total.

Details

Primary Language Turkish
Journal Section Research Articles
Authors

Nedim Karagenç

Duygu Meydancı This is me

Hakan Küçüksayan This is me

Publication Date October 24, 2015
Submission Date October 24, 2015
Published in Issue Year 2015 Volume: 42 Issue: 3

Cite

APA Karagenç, N., Meydancı, D., & Küçüksayan, H. (2015). Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması. Dicle Tıp Dergisi, 42(3), 361-367. https://doi.org/10.5798/diclemedj.0921.2015.03.0590
AMA Karagenç N, Meydancı D, Küçüksayan H. Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması. diclemedj. November 2015;42(3):361-367. doi:10.5798/diclemedj.0921.2015.03.0590
Chicago Karagenç, Nedim, Duygu Meydancı, and Hakan Küçüksayan. “Akciğer Kanseri hücre Dizilerinde Hipoksi indüklenebilir faktör-1 (HIF-1) Ve Paraoksonaz Enzim ilişkisinin araştırılması”. Dicle Tıp Dergisi 42, no. 3 (November 2015): 361-67. https://doi.org/10.5798/diclemedj.0921.2015.03.0590.
EndNote Karagenç N, Meydancı D, Küçüksayan H (November 1, 2015) Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması. Dicle Tıp Dergisi 42 3 361–367.
IEEE N. Karagenç, D. Meydancı, and H. Küçüksayan, “Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması”, diclemedj, vol. 42, no. 3, pp. 361–367, 2015, doi: 10.5798/diclemedj.0921.2015.03.0590.
ISNAD Karagenç, Nedim et al. “Akciğer Kanseri hücre Dizilerinde Hipoksi indüklenebilir faktör-1 (HIF-1) Ve Paraoksonaz Enzim ilişkisinin araştırılması”. Dicle Tıp Dergisi 42/3 (November 2015), 361-367. https://doi.org/10.5798/diclemedj.0921.2015.03.0590.
JAMA Karagenç N, Meydancı D, Küçüksayan H. Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması. diclemedj. 2015;42:361–367.
MLA Karagenç, Nedim et al. “Akciğer Kanseri hücre Dizilerinde Hipoksi indüklenebilir faktör-1 (HIF-1) Ve Paraoksonaz Enzim ilişkisinin araştırılması”. Dicle Tıp Dergisi, vol. 42, no. 3, 2015, pp. 361-7, doi:10.5798/diclemedj.0921.2015.03.0590.
Vancouver Karagenç N, Meydancı D, Küçüksayan H. Akciğer kanseri hücre dizilerinde hipoksi indüklenebilir faktör-1 (HIF-1) ve paraoksonaz enzim ilişkisinin araştırılması. diclemedj. 2015;42(3):361-7.