Mitochondrial Stat3, the need for design thinking

International Journal of Biological Sciences

Volumn 12, Issue 5, 2016, Pages 532-544

  Yang, Rui ^a   Rincon, Mercedes ^a  

^a UNIVERSITY OF VERMONT COLLEGE OF MEDICINE   (United States)

Author keywords

Stat3

Indexed keywords

CALCIUM; REACTIVE OXYGEN METABOLITE; STAT3 PROTEIN;

ANIMAL; HUMAN; METABOLISM; MITOCHONDRION;

ANIMALS; CALCIUM; HUMANS; MITOCHONDRIA; REACTIVE OXYGEN SPECIES; STAT3 TRANSCRIPTION FACTOR;

EID: 84960331383     PISSN: 14492288     EISSN: None     Source Type: Journal    
DOI: 10.7150/ijbs.15153     Document Type: Review

References (151)

1. Levy DE, Lee CK. What does Stat3 do? J Clin Invest. 2002; 109: 1143-8
2. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, et al. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994; 77: 63-71
3. Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, et al. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994; 263: 89-92
4. Zhong Z, Wen Z, Darnell JE, Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994; 264: 95-8
5. Raz R, Durbin JE, Levy DE. Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors. The Journal of biological chemistry. 1994; 269: 24391-5
6. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. The Biochemical journal. 2003; 374: 1-20
7. Xu X, Sun YL, Hoey T. Cooperative DNA binding and sequence-selective recognition conferred by the STAT amino-terminal domain. Science. 1996; 273: 794-7
8. Becker S, Groner B, Muller CW. Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature. 1998; 394: 145-51
9. Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, et al. The STAT3 isoforms alpha and beta have unique and specific functions. Nature immunology. 2004; 5: 401-9
10. Yoo JY, Huso DL, Nathans D, Desiderio S. Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell. 2002; 108: 331-44
11. Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JA, Lammers JW, et al. STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. The Journal of biological chemistry. 1996; 271: 13221-7
12. Schaefer TS, Sanders LK, Nathans D. Cooperative transcriptional activity of Jun and Stat3 beta, a short form of Stat3. Proceedings of the National Academy of Sciences of the United States of America. 1995; 92: 9097-101
13. Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, et al. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994; 263: 92-5
14. Narazaki M, Witthuhn BA, Yoshida K, Silvennoinen O, Yasukawa K, Ihle JN, et al. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 2285-9
15. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. The Biochemical journal. 1998; 334 (Pt 2): 297-314
16. Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003; 300: 2101-4
17. Guschin D, Rogers N, Briscoe J, Witthuhn B, Watling D, Horn F, et al. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. The EMBO journal. 1995; 14: 1421-9
18. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene. 2000; 19: 2628-37
19. Wen Z, Zhong Z, Darnell JE, Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995; 82: 241-50
20. Zhong Z, Wen Z, Darnell JE, Jr. Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 4806-10
21. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, et al. Function of mitochondrial Stat3 in cellular respiration. Science. 2009; 323: 793-7
22. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 2009; 324: 1713-6
23. Yang R, Lirussi D, Thornton TM, Jelley-Gibbs DM, Diehl SA, Case LK, et al. Mitochondrial Ca(2)(+) and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function. eLife. 2015; 4
24. Lachance C, Goupil S, Leclerc P. Stattic V, a STAT3 inhibitor, affects human spermatozoa through regulation of mitochondrial activity. Journal of cellular physiology. 2013; 228: 704-13
25. Zhang Q, Raje V, Yakovlev VA, Yacoub A, Szczepanek K, Meier J, et al. Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. The Journal of biological chemistry. 2013; 288: 31280-8
26. Shulga N, Pastorino JG. GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis. Journal of cell science. 2012; 125: 2995-3003
27. Szczepanek K, Chen Q, Derecka M, Salloum FN, Zhang Q, Szelag M, et al. Mitochondrial-targeted Signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species. The Journal of biological chemistry. 2011; 286: 29610-20
28. Heusch G, Musiolik J, Gedik N, Skyschally A. Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circulation research. 2011; 109: 1302-8
29. Zhou L, Too HP. Mitochondrial localized STAT3 is involved in NGF induced neurite outgrowth. PloS one. 2011; 6: e21680
30. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R. Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic research in cardiology. 2010; 105: 771-85
31. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nature reviews Cancer. 2014; 14: 736-46
32. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, et al. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proceedings of the National Academy of Sciences of the United States of America. 1997; 94: 3801-4
33. Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, et al. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. The Journal of experimental medicine. 2009; 206: 1291-301
34. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008; 452: 773-6
35. de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. The Journal of experimental medicine. 2008; 205: 1543-50
36. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, et al. GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. The EMBO journal. 2003; 22: 1325-35
37. Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, et al. The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100: 9342-7
38. Cimica V, Chen HC, Iyer JK, Reich NC. Dynamics of the STAT3 transcription factor: nuclear import dependent on Ran and importin-beta1. PloS one. 2011; 6: e20188
39. Phillips D, Reilley MJ, Aponte AM, Wang G, Boja E, Gucek M, et al. Stoichiometry of STAT3 and mitochondrial proteins: Implications for the regulation of oxidative phosphorylation by protein-protein interactions. The Journal of biological chemistry. 2010; 285: 23532-6
40. Tammineni P, Anugula C, Mohammed F, Anjaneyulu M, Larner AC, Sepuri NB. The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. The Journal of biological chemistry. 2013; 288: 4723-32
41. Qiu H, Lizano P, Laure L, Sui X, Rashed E, Park JY, et al. H11 kinase/heat shock protein 22 deletion impairs both nuclear and mitochondrial functions of STAT3 and accelerates the transition into heart failure on cardiac overload. Circulation. 2011; 124: 406-15
42. Tateno T, Asa SL, Zheng L, Mayr T, Ullrich A, Ezzat S. The FGFR4-G388R polymorphism promotes mitochondrial STAT3 serine phosphorylation to facilitate pituitary growth hormone cell tumorigenesis. PLoS genetics. 2011; 7: e1002400
43. Sarafian TA, Montes C, Imura T, Qi J, Coppola G, Geschwind DH, et al. Disruption of astrocyte STAT3 signaling decreases mitochondrial function and increases oxidative stress in vitro. PloS one. 2010; 5: e9532
44. Kang R, Loux T, Tang D, Schapiro NE, Vernon P, Livesey KM, et al. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 7031-6
45. Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nature reviews Molecular cell biology. 2012; 13: 566-78
46. 2+ uniporter gene MCU. Science signaling. 2015; 8: 23
47. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 2011; 476: 341-5
48. De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011; 476: 336-40
49. 2+ exchange. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107: 436-41
50. Crompton M, Kunzi M, Carafoli E. The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. European journal of biochemistry / FEBS. 1977; 79: 549-58
51. Tang Y, Zucker RS. Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron. 1997; 18: 483-91
52. Billups B, Forsythe ID. Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2002; 22: 5840-7
53. 2+) buffering regulates synaptic transmission between retinal amacrine cells. Journal of neurophysiology. 2002; 87: 1426-39
54. Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Molecular cell. 2012; 48: 158-67
55. Murphy MP. How mitochondria produce reactive oxygen species. The Biochemical journal. 2009; 417: 1-13
56. Shulga N, Pastorino JG. Mitoneet mediates TNFalpha-induced necroptosis promoted by exposure to fructose and ethanol. Journal of cell science. 2014; 127: 896-907
57. Zouein FA, Duhe RJ, Arany I, Shirey K, Hosler JP, Liu H, et al. Loss of STAT3 in mouse embryonic fibroblasts reveals its Janus-like actions on mitochondrial function and cell viability. Cytokine. 2014; 66: 7-16
58. Mantel C, Messina-Graham S, Moh A, Cooper S, Hangoc G, Fu XY, et al. Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype. Blood. 2012; 120: 2589-99
59. Garama DJ, Harris TJ, White CL, Rossello FJ, Abdul-Hay M, Gough DJ, et al. A synthetic lethal interaction between glutathione synthesis and mitochondrial reactive oxygen species provides a tumor specific vulnerability dependent on STAT3. Molecular and cellular biology. 2015
60. Hackenbrock CR, Chazotte B, Gupte SS. The random collision model and a critical assessment of diffusion and collision in mitochondrial electron transport. Journal of bioenergetics and biomembranes. 1986; 18: 331-68
61. Acin-Perez R, Fernandez-Silva P, Peleato ML, Perez-Martos A, Enriquez JA. Respiratory active mitochondrial supercomplexes. Molecular cell. 2008; 32: 529-39
62. Eubel H, Heinemeyer J, Braun HP. Identification and characterization of respirasomes in potato mitochondria. Plant physiology. 2004; 134: 1450-9
63. Eubel H, Heinemeyer J, Sunderhaus S, Braun HP. Respiratory chain supercomplexes in plant mitochondria. Plant physiology and biochemistry: PPB / Societe francaise de physiologie vegetale. 2004; 42: 937-42
64. Winge DR. Sealing the mitochondrial respirasome. Molecular and cellular biology. 2012; 32: 2647-52
65. Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Annals of the New York Academy of Sciences. 2005; 1047: 248-58
66. Halestrap AP. What is the mitochondrial permeability transition pore? Journal of molecular and cellular cardiology. 2009; 46: 821-31
67. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. Cardiovascular research. 2004; 61: 372-85
68. Doran E, Halestrap AP. Cytochrome c release from isolated rat liver mitochondria can occur independently of outer-membrane rupture: possible role of contact sites. The Biochemical journal. 2000; 348 Pt 2: 343-50
69. Petronilli V, Nicolli A, Costantini P, Colonna R, Bernardi P. Regulation of the permeability transition pore, a voltage-dependent mitochondrial channel inhibited by cyclosporin A. Biochimica et biophysica acta. 1994; 1187: 255-9
70. Szczepanek K, Xu A, Hu Y, Thompson J, He J, Larner AC, et al. Cardioprotective function of mitochondrial-targeted and transcriptionally inactive STAT3 against ischemia and reperfusion injury. Basic research in cardiology. 2015; 110: 53
71. Boengler K, Ungefug E, Heusch G, Schulz R. The STAT3 inhibitor stattic impairs cardiomyocyte mitochondrial function through increased reactive oxygen species formation. Current pharmaceutical design. 2013; 19: 6890-5
72. Warburg O, Wind F, Negelein E. The Metabolism of Tumors in the Body. The Journal of general physiology. 1927; 8: 519-30
73. Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria in cancer cells: what is so special about them? Trends in cell biology. 2008; 18: 165-73
74. Gough DJ, Koetz L, Levy DE. The MEK-ERK pathway is necessary for serine phosphorylation of mitochondrial STAT3 and Ras-mediated transformation. PloS one. 2013; 8: e83395
75. Yu C, Huo X, Agoston AT, Zhang X, Theiss AL, Cheng E, et al. Mitochondrial STAT3 contributes to transformation of Barrett's epithelial cells that express oncogenic Ras in a p53-independent fashion. American journal of physiology Gastrointestinal and liver physiology. 2015; 309: G146-61
76. Kang R, Tang D, Lotze MT, Zeh HJ, 3rd. AGER/RAGE-mediated autophagy promotes pancreatic tumorigenesis and bioenergetics through the IL6-pSTAT3 pathway. Autophagy. 2012; 8: 989-91
77. Kang R, Tang D. Autophagy in pancreatic cancer pathogenesis and treatment. American journal of cancer research. 2012; 2: 383-96
78. Macias E, Rao D, Carbajal S, Kiguchi K, DiGiovanni J. Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. The Journal of investigative dermatology. 2014; 134: 1971-80
79. Du L, Subauste MC, DeSevo C, Zhao Z, Baker M, Borkowski R, et al. miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers. PloS one. 2012; 7: e39167
80. Han Z, Feng J, Hong Z, Chen L, Li W, Liao S, et al. Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells. Biochemical and biophysical research communications. 2013; 435: 188-94
81. Chen RJ, Ho YS, Guo HR, Wang YJ. Long-term nicotine exposure-induced chemoresistance is mediated by activation of Stat3 and downregulation of ERK1/2 via nAChR and beta-adrenoceptors in human bladder cancer cells. Toxicological sciences: an official journal of the Society of Toxicology. 2010; 115: 118-30
82. Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, et al. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007; 109: 2293-302
83. Real PJ, Sierra A, De Juan A, Segovia JC, Lopez-Vega JM, Fernandez-Luna JL. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 2002; 21: 7611-8
84. Wen K, Fu Z, Wu X, Feng J, Chen W, Qian J. Oct-4 is required for an antiapoptotic behavior of chemoresistant colorectal cancer cells enriched for cancer stem cells: effects associated with STAT3/Survivin. Cancer letters. 2013; 333: 56-65
85. Guo L, Chen C, Shi M, Wang F, Chen X, Diao D, et al. Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition. Oncogene. 2013; 32: 5272-82
86. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008; 29: 44-56
87. Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Current opinion in immunology. 2007; 19: 281-6
88. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annual review of immunology. 2007; 25: 821-52
89. Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F, et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. International immunology. 2007; 19: 695-702
90. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008; 453: 1051-7
91. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441: 235-8
92. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Lango Allen H, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nature genetics. 2014; 46: 812-4
93. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015; 125: 591-9
94. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009; 30: 92-107
95. Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annual review of pathology. 2013; 8: 477-512
96. Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012; 119: 3997-4008
97. Crotty S. Follicular helper CD4 T cells (TFH). Annual review of immunology. 2011; 29: 621-63
98. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008; 29: 138-49
99. Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010; 32: 605-15
100. Steward-Tharp SM, Laurence A, Kanno Y, Kotlyar A, Villarino AV, Sciume G, et al. A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3. Blood. 2014; 123: 2978-87
101. Walker S, Wang C, Walradt T, Hong BS, Tanner JR, Levinsohn JL, et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood. 2015
102. Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. The Journal of experimental medicine. 2009; 206: 69-78
103. Diehl S, Chow CW, Weiss L, Palmetshofer A, Twardzik T, Rounds L, et al. Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. The Journal of experimental medicine. 2002; 196: 39-49
104. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature immunology. 2007; 8: 967-74
105. Shulman Z, Gitlin AD, Weinstein JS, Lainez B, Esplugues E, Flavell RA, et al. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science. 2014; 345: 1058-62
106. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012; 36: 68-78
107. Cui W, Liu Y, Weinstein JS, Craft J, Kaech SM. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity. 2011; 35: 792-805
108. Siegel AM, Heimall J, Freeman AF, Hsu AP, Brittain E, Brenchley JM, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity. 2011; 35: 806-18
109. Campello S, Lacalle RA, Bettella M, Manes S, Scorrano L, Viola A. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. The Journal of experimental medicine. 2006; 203: 2879-86
110. Morlino G, Barreiro O, Baixauli F, Robles-Valero J, Gonzalez-Granado JM, Villa-Bellosta R, et al. Miro-1 links mitochondria and microtubule Dynein motors to control lymphocyte migration and polarity. Molecular and cellular biology. 2014; 34: 1412-26
111. Sanchez-Madrid F, Serrador JM. Mitochondrial redistribution: adding new players to the chemotaxis game. Trends in immunology. 2007; 28: 193-6
112. Erlich TH, Yagil Z, Kay G, Peretz A, Migalovich-Sheikhet H, Tshori S, et al. Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis. The Journal of allergy and clinical immunology. 2014; 134: 460-9
113. Yu CR, Lee YS, Mahdi RM, Surendran N, Egwuagu CE. Therapeutic targeting of STAT3 (signal transducers and activators of transcription 3) pathway inhibits experimental autoimmune uveitis. PloS one. 2012; 7: e29742
114. Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert opinion on investigational drugs. 2009; 18: 45-56
115. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anti-cancer drugs. 2005; 16: 601-7
116. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Science translational medicine. 2015; 7: 314ra185
117. Leong PL, Andrews GA, Johnson DE, Dyer KF, Xi S, Mai JC, et al. Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100: 4138-43
118. Sen M, Thomas SM, Kim S, Yeh JI, Ferris RL, Johnson JT, et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer discovery. 2012; 2: 694-705
119. Turkson J, Ryan D, Kim JS, Zhang Y, Chen Z, Haura E, et al. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. The Journal of biological chemistry. 2001; 276: 45443-55
120. Vultur A, Cao J, Arulanandam R, Turkson J, Jove R, Greer P, et al. Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells. Oncogene. 2004; 23: 2600-16
121. Turkson J, Kim JS, Zhang S, Yuan J, Huang M, Glenn M, et al. Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Molecular cancer therapeutics. 2004; 3: 261-9
122. Zhang X, Yue P, Page BD, Li T, Zhao W, Namanja AT, et al. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 9623-8
123. Zhang Q, Zhang C, He J, Guo Q, Hu D, Yang X, et al. STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2015; 36: 2135-42
124. Pan Y, Zhou F, Zhang R, Claret FX. Stat3 inhibitor Stattic exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma. PloS one. 2013; 8: e54565
125. Adachi M, Cui C, Dodge CT, Bhayani MK, Lai SY. Targeting STAT3 inhibits growth and enhances radiosensitivity in head and neck squamous cell carcinoma. Oral oncology. 2012; 48: 1220-6
126. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chemistry & biology. 2006; 13: 1235-42
127. Bill MA, Fuchs JR, Li C, Yui J, Bakan C, Benson DM, Jr., et al. The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. Molecular cancer. 2010; 9: 165
128. Lin L, Hutzen B, Zuo M, Ball S, Deangelis S, Foust E, et al. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer research. 2010; 70: 2445-54
129. Mackenzie GG, Huang L, Alston N, Ouyang N, Vrankova K, Mattheolabakis G, et al. Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice. PloS one. 2013; 8: e61532
130. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer research. 2003; 63: 1270-9
131. Ishdorj G, Johnston JB, Gibson SB. Inhibition of constitutive activation of STAT3 by curcurbitacin-I (JSI-124) sensitized human B-leukemia cells to apoptosis. Molecular cancer therapeutics. 2010; 9: 3302-14
132. Premkumar DR, Jane EP, Agostino NR, Scialabba JL, Pollack IF. Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. Journal of carcinogenesis. 2010; 9
133. Su Y, Li G, Zhang X, Gu J, Zhang C, Tian Z, et al. JSI-124 inhibits glioblastoma multiforme cell proliferation through G(2)/M cell cycle arrest and apoptosis augment. Cancer biology & therapy. 2008; 7: 1243-9
134. Chen CL, Hsieh FC, Lieblein JC, Brown J, Chan C, Wallace JA, et al. Stat3 activation in human endometrial and cervical cancers. British journal of cancer. 2007; 96: 591-9
135. Shi X, Franko B, Frantz C, Amin HM, Lai R. JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells. British journal of haematology. 2006; 135: 26-32
136. Zhang T, Li Y, Park KA, Byun HS, Won M, Jeon J, et al. Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis. Autophagy. 2012; 8: 559-76
137. Kim HJ, Park JH, Kim JK. Cucurbitacin-I, a natural cell-permeable triterpenoid isolated from Cucurbitaceae, exerts potent anticancer effect in colon cancer. Chemico-biological interactions. 2014; 219: 1-8
138. Wang LH, Kirken RA, Erwin RA, Yu CR, Farrar WL. JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation of IL-2-mediated T cell response. Journal of immunology. 1999; 162: 3897-904
139. Levitzki A, Gazit A. Tyrosine kinase inhibition: an approach to drug development. Science. 1995; 267: 1782-8
140. Du W, Hong J, Wang YC, Zhang YJ, Wang P, Su WY, et al. Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway. Journal of cellular and molecular medicine. 2012; 16: 1878-88
141. Huang C, Cao J, Huang KJ, Zhang F, Jiang T, Zhu L, et al. Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer science. 2006; 97: 1417-23
142. Miyamoto N, Sugita K, Goi K, Inukai T, Lijima K, Tezuka T, et al. The JAK2 inhibitor AG490 predominantly abrogates the growth of human B-precursor leukemic cells with 11q23 translocation or Philadelphia chromosome. Leukemia. 2001; 15: 1758-68
143. De Vos J, Jourdan M, Tarte K, Jasmin C, Klein B. JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. British journal of haematology. 2000; 109: 823-8
144. Guo Z, Jiang H, Xu X, Duan W, Mattson MP. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. The Journal of biological chemistry. 2008; 283: 1754-63
145. Meier JA, Larner AC. Toward a new STATe: the role of STATs in mitochondrial function. Seminars in immunology. 2014; 26: 20-8
146. Szczepanek K, Lesnefsky EJ, Larner AC. Multi-tasking: nuclear transcription factors with novel roles in the mitochondria. Trends in cell biology. 2012; 22: 429-37
147. Szczepanek K, Chen Q, Larner AC, Lesnefsky EJ. Cytoprotection by the modulation of mitochondrial electron transport chain: the emerging role of mitochondrial STAT3. Mitochondrion. 2012; 12: 180-9
148. Zouein FA, Altara R, Chen Q, Lesnefsky EJ, Kurdi M, Booz GW. Pivotal Importance of STAT3 in Protecting the Heart from Acute and Chronic Stress: New Advancement and Unresolved Issues. Front Cardiovasc Med. 2015; 2: 36
149. Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG, Subrayan S, et al. Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. American journal of physiology Heart and circulatory physiology. 2010; 299: H1265-70
150. Lemoine S, Zhu L, Legallois D, Massetti M, Manrique A, Hanouz JL. Atorvastatin-induced cardioprotection of human myocardium is mediated by the inhibition of mitochondrial permeability transition pore opening via tumor necrosis factor-alpha and Janus kinase/signal transducers and activators of transcription pathway. Anesthesiology. 2013; 118: 1373-84
151. Yang Y, Duan W, Jin Z, Yi W, Yan J, Zhang S, et al. JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. Journal of pineal research. 2013; 55: 275-86.