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Aging and Disease    2014, Vol. 5 Issue (3) : 203-211     DOI: 10.14336/AD.2014.0500203
Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases
Atsuko Nakanishi, Yoko Wada, Yasuko Kitagishi, Satoru Matsuda
Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
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Accumulating evidence has revealed that thePI3K/AKT/PTENpathway acts as a pivotal determinant of cell fate regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. NADPH oxidase (NOX) family of enzymes generates the ROS. The regulation of NOX enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. Cells are continuously exposed to the ROS, which represent mutagens and are thought to be a major contributor to several diseases including cancer and aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, the roles of oxidative stress in PI3K/AKT/PTEN signaling are summarized with a focus on the links between the pathways and NOX protein in several diseases including cancer and aging.

Keywords PTEN      PI3K      AKT      ROS      PPAR      WRN      SIRT1      cell signaling     
Corresponding Authors: Satoru Matsuda   
Issue Date: 10 May 2014
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Atsuko Nakanishi
Yoko Wada
Yasuko Kitagishi
Satoru Matsuda
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Atsuko Nakanishi,Yoko Wada,Yasuko Kitagishi, et al. Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases[J]. Aging and Disease, 2014, 5(3): 203-211.
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[1] Salvemini D, Cuzzocrea S(2002). Oxidative stress in septic shock and disseminated intravascular coagulation. Free Radic Biol Med, 33:1173-1185
[2] Ballard JW(2005). Drosophila simulans as a novel model for studying mitochondrial metabolism and aging. Exp Gerontol, 40:763-773
[3] Zhang Y, Du Y, Le W, Wang K, Kieffer N, Zhang J(2011). Redox control of the survival of healthy and diseased cells. Antioxid Redox Signal, 15:2867-2908
[4] Scatena R(2012). Mitochondria and cancer: a growing role in apoptosis, cancer cell metabolism and dedifferentiation. Adv Exp Med Biol, 942:287-308
[5] Wu RF, Ma Z, Myers DP, Terada LS(2007). HIV-1 Tat activates dual Nox pathways leading to independent activation of ERK and JNK MAP kinases. J Biol Chem, 282:37412-37419
[6] San Martín A, Griendling KK(2010). Redox control of vascular smooth muscle migration. Antioxid Redox Signal, 12:625-640
[7] Weyemi U, Redon CE, Parekh PR, Dupuy C, Bonner WM(2013). NADPH Oxidases NOXs and DUOXs as putative targets for cancer therapy. Anticancer Agents Med Chem, 13:502-514
[8] Roberts CK, Sindhu KK(2009). Oxidative stress and metabolic syndrome. Life Sci, 84:705-712
[9] Leonarduzzi G, Sottero B, Testa G, Biasi F, Poli G(2011). New insights into redox-modulated cell signaling. Curr Pharm Des, 17:3994-4006
[10] Xu J, Tian W, Ma X(2011). The molecular mechanism underlying morphine-induced AKT activation: roles of protein phosphatases and reactive oxygen species. Cell Biochem Biophys, 61:303-311
[11] Maehama T, Taylor GS, Dixon JE(2001). PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem, 70:247-279
[12] Howes AL, Arthur JF, Zhang T(2003). AKT-mediated cardiomyocyte survival pathways are compromised by G alpha q-induced phosphoinositide 4,5-bisphosphate depletion. J Biol Chem, 278:40343-40351
[13] Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA(2012). Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit Rev Oncog, 17:9-95
[14] Castaneda CA, Cortes-Funes H, Gomez HL, Ciruelos EM(2010). The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer. Cancer Metastasis Rev, 29:751-759
[15] Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C(2006). Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Int J Cancer, 118:2390-2398
[16] Harikumar KB, Aggarwal BB(2008). Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle, 7:1020-1035
[17] Yoshida H, Okumura N, Kitagishi Y, Nishimura Y, Matsuda S(2011). Ethanol extract of Rosemary repressed PTEN expression in K562 culture cells. Int J appl Boil pharm Technol, 2:316-322
[18] Weng LP, Brown JL, Eng C(2001). PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet, 10:599-604
[19] Carver DJ, Gaston B, Deronde K, Palmer LA(2007). AKT-mediated activation of HIF-1 in pulmonary vascular endothelial cells by S-nitrosoglutathione. Am J Respir Cell Mol Biol, 37:255-263
[20] Li YM, Zhou BP, Deng J, Pan Y, Hay N, Hung MC(2005). A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phosphatidylinositol-3 kinase/AKT in HER2 overexpressing cells. Cancer Res, 65:3257-3263
[21] Kitagishi Y, Matsuda S(2013). Redox regulation of tumor suppressor PTEN in cancer and aging (Review)Int J Mol Med, 31:511-515
[22] Maghzal GJ, Krause KH, Stocker R, Jaquet V(2012). Detection of reactive oxygen species derived from the family of NOX NADPH oxidases. Free Radic Biol Med, 53:1903-1918
[23] El-Benna J, Dang PM, Gougerot-Pocidalo MA, Marie JC, Braut-Boucher F(2009). p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Exp Mol Med, 41:217-225
[24] Chatterjee S, Browning EA, Hong N, DeBolt K, Sorokina EM, Liu W, Birnbaum MJ, Fisher AB(2012). Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS. Am J Physiol Heart Circ Physiol, 302:H105-H114
[25] Ren Z, Raucci FJJr, Browe DM, Baumgarten CM(2008). Regulation of swelling-activated Cl(-) current by angiotensin II signalling and NADPH oxidase in rabbit ventricle. Cardiovasc Res, 77:73-80
[26] Ngkelo A, Meja K, Yeadon M, Adcock I, Kirkham PA(2012). LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling. J Inflamm (Lond)9:1
[27] Jee HJ, Kim HJ, Kim AJ, Bae YS, Bae SS, Yun J(2009). UV light induces premature senescence in Akt1-null mouse embryonic fibroblasts by increasing intracellular levels of ROS. Biochem Biophys Res Commun, 383:358-362
[28] Bäumer AT, Ten Freyhaus H, Sauer H, Wartenberg M, Kappert K, Schnabel P, Konkol C, Hescheler J, Vantler M, Rosenkranz S(2008). Phosphatidylinositol 3-kinase-dependent membrane recruitment of Rac-1 and p47phox is critical for alpha-platelet-derived growth factor receptor-induced production of reactive oxygen species. J Biol Chem, 283:7864-7876
[29] Lee SB, Bae IH, Bae YS, Um HD(2006). Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death. J Biol Chem, 281:36228-36235
[30] Yuan H, Lu Y, Huang X, He Q, Man Y, Zhou Y, Wang S, Li J(2010). Suppression of NADPH oxidase 2 substantially restores glucose-induced dysfunction of pancreatic NIT-1 cells. FEBS J, 277:5061-5071
[31] Barbieri SS, Ruggiero L, Tremoli E, Weksler BB(2008). Suppressing PTEN activity by tobacco smoke plus interleukin-1beta modulates dissociation of VE-cadherin/beta-catenin complexes in endothelium. Arterioscler Thromb Vasc Biol, 28:732-738
[32] Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP(2003). Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J, 22:5501-5510
[33] Kim JW, Kang KH, Burrola P, MAKTW, Lemke G(2008). Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium. Genes Dev, 22:3147-3157
[34] Zu L, Zheng X, Wang B(2011). Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion. Am J Physiol Heart Circ Physiol, 300:H2177-H2186
[35] Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG(2002). Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem, 277:20336-20342
[36] Matsuda M, Takeshita K, Kurokawa T(2011). Crystal structure of the cytoplasmic phosphatase and tensin homolog (PTEN)-like region of Ciona intestinalis voltage-sensing phosphatase provides insight into substrate specificity and redox regulation of the phosphoinositide phosphatase activity. J Biol Chem, 286:23368-23377
[37] Kamata T(2009). Roles of Nox1 and other Nox isoforms in cancer development. Cancer Sci, 100:1382-1388
[38] Shinohara M, Shang WH, Kubodera M, Harada S, Mitsushita J, Kato M, Miyazaki H, Sumimoto H, Kamata T(2007). Nox1 redox signaling mediates oncogenic Ras-induced disruption of stress fibers and focal adhesions by down-regulating Rho. J Biol Chem, 282:17640-17648
[39] Ock CY, Kim EH, Choi DJ, Lee HJ, Hahm KB, Chung MH(2012). 8-Hydroxydeoxyguanosine: not mere biomarker for oxidative stress, but remedy for oxidative stress-implicated gastrointestinal diseases. World J Gastroenterol, 18:302-308
[40] Cefalu WT(2006). Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance to the human condition. ILAR J, 47:186-198
[41] Yuan H, Zhang X, Huang X, Lu Y, Tang W, Man Y, Wang S, Xi J, Li J(2010). NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PLoS One, 5:e15726
[42] Muralikrishna Adibhatla R, Hatcher JF(2006). Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med, 40:376-387
[43] Adibhatla RM, Hatcher JF(2008). Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. BMB Rep, 41:560-567
[44] Wood LG, Wark PA, Garg ML(2010). Antioxidant and anti-inflammatory effects of resveratrol in airway disease. Antioxid Redox Signal, 13:1535-1548
[45] Chiu-Ugalde J, Wirth EK, Klein MO, Sapin R, Fradejas-Villar N, Renko K, Schomburg L, Köhrle J, Schweizer U(2012). Thyroid function is maintained despite increased oxidative stress in mice lacking selenoprotein biosynthesis in thyroid epithelial cells. Antioxid Redox Signal, 17:902-913
[46] Weyemi U, Caillou B, Talbot M, Ameziane-El-Hassani R, Lacroix L, Lagent-Chevallier O, Al Ghuzlan A, Roos D, Bidart JM, Virion A, Schlumberger M, Dupuy C(2010). Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues. Endocr Relat Cancer, 17:27-37
[47] Ishiyama J, Taguchi R, Yamamoto A, Murakami K(2010). Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells. Atherosclerosis, 209:118-124
[48] Laddha NC, Dwivedi M, Mansuri MS, Gani AR, Ansarullah M, Ramachandran AV, Dalai S, Begum R(2013). Vitiligo: interplay between oxidative stress and immune system. Exp Dermatol, 22:245-250
[49] Wirtenberger M, Frank B, Hemminki K, Klaes R, Schmutzler RK, Wappenschmidt B, Meindl A, Kiechle M, Arnold N, Weber BH, Niederacher D, Bartram CR, Burwinkel B(2006). Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer. Carcinogenesis, 27:1655-1660
[50] Labbé A, Lafleur VN, Patten DA, Robitaille GA, Garand C, Lamalice L, Lebel M, Richard DE(2012). The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity. Exp Cell Res, 318:1620-1632
[51] Shafee N, Kaluz S, Ru N, Stanbridge EJ(2009). PI3K/Akt activity has variable cell-specific effects on expression of HIF target genes, CA9 and VEGF, in human cancer cell lines. Cancer Lett, 282:109-115
[52] Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ(2000). Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev, 14:391-396
[53] Massip L, Garand C, Paquet ER(2010). Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J, 24:158-172
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