STAT3-mediated metabolic reprograming in cellular transformation and implications for drug resistance

Frontiers in Oncology

Volumn 5, Issue JUN, 2015, Pages

  Poli, Valeria ^a   Camporeale, Annalisa ^a  

^a UNIVERSITY OF TURIN   (Italy)

Author keywords

Drug resistance; Malignant transformation; Metabolism; Mitochondria; STAT3 transcription factor

Indexed keywords

EID: 84934291311     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2015.00121     Document Type: Short Survey

References (117)

1. Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem (2007) 282:20059-63. doi: 10.1074/jbc.R700016200
2. Levy DE, Lee CK. What does Stat3 do? J Clin Invest (2002) 109:1143-8. doi:10.1172/JCI200215650
3. Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol (1997) 17:6508-16.
4. Hazan-Halevy I, Harris D, Liu Z, Liu J, Li P, Chen X, et al. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood (2010) 115:2852-63. doi:10.1182/blood-2009-10-230060
5. Lim CP, Cao X. Serine phosphorylation and negative regulation of Stat3 by JNK. J Biol Chem (1999) 274:31055-61. doi:10.1074/jbc.274.43.31055
6. 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. doi:10.1016/0092-8674(95)90311-9
7. 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. doi:10.1126/science.1164551
8. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science (2009) 324:1713-6. doi:10.1126/science.1171721
9. Lee H, Zhang P, Herrmann A, Yang C, Xin H, Wang Z, et al. Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc Natl Acad Sci U S A (2012) 109:7765-9. doi:10.1073/pnas.1205132109
10. Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell (2013) 23:839-52. doi:10.1016/j.ccr.2013.04.008
11. Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B, et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci U S A (2010) 107:21499-504. doi:10.1073/pnas.1016147107
12. Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat Immunol (2003) 4:1169-76. doi:10.1038/ni1012
13. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol (2005) 5:593-605. doi:10.1038/nri1667
14. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer (2009) 9:798-809. doi:10.1038/nrc2734
15. Couronne L, Scourzic L, Pilati C, Della Valle V, Duffourd Y, Solary E, et al. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model. Haematologica (2013) 98:1748-52. doi:10.3324/haematol.2013.085068
16. Fasan A, Kern W, Grossmann V, Haferlach C, Haferlach T, Schnittger S. STAT3 mutations are highly specific for large granular lymphocytic leukemia. Leukemia (2013) 27:1598-600. doi:10.1038/leu.2012.350
17. Jerez A, Clemente MJ, Makishima H, Koskela H, Leblanc F, Peng Ng K, et al. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood (2012) 120:3048-57. doi:10.1182/blood-2012-06-435297
18. Koskela HL, Eldfors S, Ellonen P, Van Adrichem AJ, Kuusanmaki H, Andersson EI, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med (2012) 366:1905-13. doi:10.1056/NEJMoa1114885
19. Ohgami RS, Ma L, Merker JD, Martinez B, Zehnder JL, Arber DA. STAT3 mutations are frequent in CD30+ T-cell lymphomas and T-cell large granular lymphocytic leukemia. Leukemia (2013) 27:2244-7. doi:10.1038/leu.2013.104
20. Pilati C, Amessou M, Bihl MP, Balabaud C, Nhieu JT, Paradis V, et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med (2011) 208:1359-66. doi:10.1084/jem.20110283
21. Frank DA, Mahajan S, Ritz J. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest (1997) 100:3140-8. doi:10.1172/JCI119869
22. Li L, Shaw PE. Elevated activity of STAT3C due to higher DNA binding affinity of phosphotyrosine dimer rather than covalent dimer formation. J Biol Chem (2006) 281:33172-81. doi:10.1074/jbc.M606940200
23. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell (1999) 98:295-303. doi:10.1016/S0092-8674(00)81959-5
24. Demaria M, Misale S, Giorgi C, Miano V, Camporeale A, Campisi J, et al. STAT3 can serve as a hit in the process of malignant transformation of primary cells. Cell Death Differ (2012) 19:1390-7. doi:10.1038/cdd.2012.20
25. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell (2010) 140:883-99. doi:10.1016/j.cell.2010.01.025
26. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr. Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol (1998) 18:2553-8.
27. Demaria M, Giorgi C, Lebiedzinska M, Esposito G, D'Angeli L, Bartoli A, et al. A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging (Albany NY) (2010) 2:823-42.
28. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (2009) 324:1029-33. doi:10.1126/science.1160809
29. Niu G, Briggs J, Deng J, Ma Y, Lee H, Kortylewski M, et al. Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1alpha RNA expression in both tumor cells and tumor-associated myeloid cells. Mol Cancer Res (2008) 6:1099-105. doi:10.1158/1541-7786.MCR-07-2177
30. Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene (2005) 24:5552-60. doi:10.1038/sj.onc.1208719
31. Anglesio MS, George J, Kulbe H, Friedlander M, Rischin D, Lemech C, et al. IL6-STAT3-HIF signaling and therapeutic response to the angiogenesis inhibitor sunitinib in ovarian clear cell cancer. Clin Cancer Res (2011) 17:2538-48. doi:10.1158/1078-0432.CCR-10-3314
32. Jung JE, Lee HG, Cho IH, Chung DH, Yoon SH, Yang YM, et al. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J (2005) 19:1296-8. doi:10.1096/fj.04-3099fje
33. Cho KH, Choi MJ, Jeong KJ, Kim JJ, Hwang MH, Shin SC, et al. A ROS/STAT3/HIF-1alpha signaling cascade mediates EGF-induced TWIST1 expression and prostate cancer cell invasion. Prostate (2014) 74:528-36. doi:10.1002/pros.22776
34. Pawlus MR, Wang L, Murakami A, Dai G, Hu CJ. STAT3 or USF2 contributes to HIF target gene specificity. PLoS One (2013) 8:e72358. doi:10.1371/journal.pone.0072358
35. Pawlus MR, Wang L, Hu CJ. STAT3 and HIF1alpha cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells. Oncogene (2014) 33:1670-9. doi:10.1038/onc.2013.115
36. Gao X, Wang H, Yang JJ, Liu X, Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell (2012) 45:598-609. doi:10.1016/j.molcel.2012.01.001
37. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell (2011) 145:732-44. doi:10.1016/j.cell.2011.03.054
38. Demaria M, Poli V. PKM2, STAT3 and HIF-1alpha: the Warburg's vicious circle. JAKSTAT (2012) 1:194-6. doi:10.4161/jkst.20662
39. Couto JP, Daly L, Almeida A, Knauf JA, Fagin JA, Sobrinho-Simoes M, et al. STAT3 negatively regulates thyroid tumorigenesis. Proc Natl Acad Sci U S A (2012) 109:E2361-70. doi:10.1073/pnas.1201232109
40. Musteanu M, Blaas L, Mair M, Schlederer M, Bilban M, Tauber S, et al. Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology (2010) 138(1003-11):e1-5. doi:10.1053/j.gastro.2009.11.049
41. Grabner B, Schramek D, Mueller KM, Moll HP, Svinka J, Hoffmann T, et al. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat Commun (2015) 6:6285. doi:10.1038/ncomms7285
42. Bernier M, Paul RK, Martin-Montalvo A, Scheibye-Knudsen M, Song S, He HJ, et al. Negative regulation of STAT3 protein-mediated cellular respiration by SIRT1 protein. J Biol Chem (2011) 286:19270-9. doi:10.1074/jbc.M110.200311
43. Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1alpha destabilization. Cancer Cell (2011) 19:416-28. doi:10.1016/j.ccr.2011.02.014
44. Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab (2006) 3:267-75. doi:10.1016/j.cmet.2006.02.009
45. Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med (2004) 10:168-74. doi:10.1038/nm980
46. Nie Y, Erion DM, Yuan Z, Dietrich M, Shulman GI, Horvath TL, et al. STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat Cell Biol (2009) 11:492-500. doi:10.1038/ncb1857
47. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell (2008) 14:312-23. doi:10.1016/j.ccr.2008.09.001
48. Wang B, Hsu SH, Frankel W, Ghoshal K, Jacob ST. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology (2012) 56:186-97. doi:10.1002/hep.25632
49. Austin S, Klimcakova E, St-Pierre J. Impact of PGC-1alpha on the topology and rate of superoxide production by the mitochondrial electron transport chain. Free Radic Biol Med (2011) 51:2243-8. doi:10.1016/j.freeradbiomed.2011.08.036
50. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A (2009) 106:20405-10. doi:10.1073/pnas.0911570106
51. Jung JE, Kim GS, Narasimhan P, Song YS, Chan PH. Regulation of Mn-superoxide dismutase activity and neuroprotection by STAT3 in mice after cerebral ischemia. J Neurosci (2009) 29:7003-14. doi:10.1523/JNEUROSCI.1110-09.2009
52. Storz P. Reactive oxygen species in tumor progression. Front Biosci (2005) 10:1881-96. doi:10.2741/1667
53. Kim JW, Gao P, Liu YC, Semenza GL, Dang CV. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol (2007) 27:7381-93. doi:10.1128/MCB.00440-07
54. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem (2000) 275:21797-800. doi:10.1074/jbc.C000023200
55. 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 Res Cardiol (2010) 105:771-85. doi:10.1007/s00395-010-0124-1
56. 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. Proc Natl Acad Sci U S A (2003) 100:9342-7. doi:10.1073/pnas.1633516100
57. Huang G, Lu H, Hao A, Ng DC, Ponniah S, Guo K, et al. GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I. Mol Cell Biol (2004) 24:8447-56. doi:10.1128/MCB.24.19.8447-8456.2004
58. Shulga N, Pastorino JG. GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis. J Cell Sci (2012) 125:2995-3003. doi:10.1242/jcs.103093
59. 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. doi:10.1161/CIRCULATIONAHA.110.013847
60. 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. doi:10.1371/journal.pone.0009532
61. Zhou L, Too HP. Mitochondrial localized STAT3 is involved in NGF induced neurite outgrowth. PLoS One (2011) 6:e21680. doi:10.1371/journal.pone.0021680
62. 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. doi:10.1371/journal.pone.0083395
63. 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. J Biol Chem (2011) 286:29610-20. doi:10.1074/jbc.M111.226209
64. Heusch G, Musiolik J, Gedik N, Skyschally A. Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res (2011) 109:1302-8. doi:10.1161/CIRCRESAHA.111.255604
65. Gough DJ, Marie IJ, Lobry C, Aifantis I, Levy DE. STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation. Blood (2014) 124:2252-61. doi:10.1182/blood-2013-02-484196
66. Qin HR, Kim HJ, Kim JY, Hurt EM, Klarmann GJ, Kawasaki BT, et al. Activation of signal transducer and activator of transcription 3 through a phosphomimetic serine 727 promotes prostate tumorigenesis independent of tyrosine 705 phosphorylation. Cancer Res (2008) 68:7736-41. doi:10.1158/0008-5472.CAN-08-1125
67. Yeh YT, Ou-Yang F, Chen IF, Yang SF, Wang YY, Chuang HY, et al. STAT3 ser727 phosphorylation and its association with negative estrogen receptor status in breast infiltrating ductal carcinoma. Int J Cancer (2006) 118:2943-7. doi:10.1002/ijc.21771
68. 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. J Biol Chem (2013) 288:31280-8. doi:10.1074/jbc.M113.505057
69. 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 Genet (2011) 7:e1002400. doi:10.1371/journal.pgen.1002400
70. Macias E, Rao D, Carbajal S, Kiguchi K, Digiovanni J. Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. J Invest Dermatol (2014) 134:1971-80. doi:10.1038/jid.2014.68
71. 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. J Biol Chem (2010) 285:23532-6. doi:10.1074/jbc.C110.152652
72. 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. doi:10.1371/journal.pone.0020188
73. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell (2002) 108:153-64. doi:10.1016/S0092-8674(02)00625-6
74. Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res (2000) 256:42-9. doi:10.1006/excr.2000.4838
75. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov (2009) 8:579-91. doi:10.1038/nrd2803
76. Patterson SD, Spahr CS, Daugas E, Susin SA, Irinopoulou T, Koehler C, et al. Mass spectrometric identification of proteins released from mitochondria undergoing permeability transition. Cell Death Differ (2000) 7:137-44. doi:10.1038/sj.cdd.4400640
77. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol (2001) 3:E255-63. doi:10.1038/ncb1101-e255
78. Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol (2012) 8:999-1014. doi:10.2217/fon.12.86
79. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med (2002) 53:615-27. doi:10.1146/annurev.med.53.082901.103929
80. Garraway LA, Janne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov (2012) 2:214-26. doi:10.1158/2159-8290.CD-12-0012
81. Wilson TR, Johnston PG, Longley DB. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets (2009) 9:307-19. doi:10.2174/156800909788166547
82. Sierra JR, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol Cancer (2010) 9:75. doi:10.1186/1476-4598-9-75
83. Ikuta K, Takemura K, Kihara M, Nishimura M, Ueda N, Naito S, et al. Overexpression of constitutive signal transducer and activator of transcription 3 mRNA in cisplatin-resistant human non-small cell lung cancer cells. Oncol Rep (2005) 13:217-22. doi:10.3892/or.13.2.217
84. Leeman-Neill RJ, Wheeler SE, Singh SV, Thomas SM, Seethala RR, Neill DB, et al. Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3. Carcinogenesis (2009) 30:1848-56. doi:10.1093/carcin/bgp211
85. Fletcher S, Turkson J, Gunning PT. Molecular approaches towards the inhibition of the signal transducer and activator of transcription 3 (Stat3) protein. ChemMedChem (2008) 3:1159-68. doi:10.1002/cmdc.200800123
86. Barre B, Vigneron A, Perkins N, Roninson IB, Gamelin E, Coqueret O. The STAT3 oncogene as a predictive marker of drug resistance. Trends Mol Med (2007) 13:4-11. doi:10.1016/j.molmed.2006.11.001
87. Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K, Kishimoto T. Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. J Clin Invest (1997) 99:2898-905. doi:10.1172/JCI119484
88. Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res (2002) 62:3351-5.
89. Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, et al. Role of Stat3 in regulating p53 expression and function. Mol Cell Biol (2005) 25:7432-40. doi:10.1128/MCB.25.17.7432-7440.2005
90. Cieply B, Farris J, Denvir J, Ford HL, Frisch SM. Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and grainyhead-like-2. Cancer Res (2013) 73:6299-309. doi:10.1158/0008-5472.CAN-12-4082
91. Clarhaut J, Gemmill RM, Potiron VA, Ait-Si-Ali S, Imbert J, Drabkin HA, et al. ZEB-1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells. Neoplasia (2009) 11:157-66. doi:10.1593/neo.81074
92. Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC, et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem (2012) 287:5819-32. doi:10.1074/jbc.M111.295964
93. Frassanito MA, Cusmai A, Iodice G, Dammacco F. Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood (2001) 97:483-9. doi:10.1182/blood.V97.2.483
94. Schwarze MM, Hawley RG. Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res (1995) 55:2262-5.
95. Borsellino N, Belldegrun A, Bonavida B. Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res (1995) 55:4633-9.
96. Alas S, Bonavida B. Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res (2001) 61:5137-44.
97. Schwab G, Siegall CB, Aarden LA, Neckers LM, Nordan RP. Characterization of an interleukin-6-mediated autocrine growth loop in the human multiple myeloma cell line, U266. Blood (1991) 77:587-93.
98. Ara T, Nakata R, Sheard MA, Shimada H, Buettner R, Groshen SG, et al. Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. Cancer Res (2013) 73:3852-64. doi:10.1158/0008-5472.CAN-12-2353
99. Klampfer L. Signal transducers and activators of transcription (STATs): novel targets of chemopreventive and chemotherapeutic drugs. Curr Cancer Drug Targets (2006) 6:107-21. doi:10.2174/156800906776056491
100. 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. doi:10.1371/journal.pone.0054565
101. Huang S, Chen M, Shen Y, Shen W, Guo H, Gao Q, et al. Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells. Cancer Lett (2012) 315:198-205. doi:10.1016/j.canlet.2011.10.011
102. Lau CK, Yang ZF, Lam SP, Lam CT, Ngai P, Tam KH, et al. Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma. Cancer Biol Ther (2007) 6:1900-7. doi:10.4161/cbt.6.12.4970
103. 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. doi:10.1038/sj.onc.1206004
104. Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell (2014) 26:207-21. doi:10.1016/j.ccr.2014.05.019
105. Yoon S, Woo SU, Kang JH, Kim K, Kwon MH, Park S, et al. STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells. Autophagy (2010) 6:1125-38. doi:10.4161/auto.6.8.13547
106. Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol (1998) 275:C1640-52.
107. Waris G, Huh KW, Siddiqui A. Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. Mol Cell Biol (2001) 21:7721-30. doi:10.1128/MCB.21.22.7721-7730.2001
108. Carballo M, Conde M, El Bekay R, Martin-Nieto J, Camacho MJ, Monteseirin J, et al. Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes. J Biol Chem (1999) 274:17580-6. doi:10.1074/jbc.274.25.17580
109. Li L, Cheung SH, Evans EL, Shaw PE. Modulation of gene expression and tumor cell growth by redox modification of STAT3. Cancer Res (2010) 70:8222-32. doi:10.1158/0008-5472.CAN-10-0894
110. Xie Y, Kole S, Precht P, Pazin MJ, Bernier M. S-glutathionylation impairs signal transducer and activator of transcription 3 activation and signaling. Endocrinology (2009) 150:1122-31. doi:10.1210/en.2008-1241
111. Chandra J, Samali A, Orrenius S. Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med (2000) 29:323-33. doi:10.1016/S0891-5849(00)00302-6
112. Hampton MB, Fadeel B, Orrenius S. Redox regulation of the caspases during apoptosis. Ann N Y Acad Sci (1998) 854:328-35. doi:10.1111/j.1749-6632.1998.tb09913.x
113. Shacter E, Williams JA, Hinson RM, Senturker S, Lee YJ. Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis. Blood (2000) 96:307-13.
114. Lee YJ, Shacter E. Oxidative stress inhibits apoptosis in human lymphoma cells. J Biol Chem (1999) 274:19792-8. doi:10.1074/jbc.274.28.19792
115. Venkatasubbarao K, Peterson L, Zhao S, Hill P, Cao L, Zhou Q, et al. Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer. Mol Cancer (2013) 12:104. doi:10.1186/1476-4598-12-104
116. Barbosa IA, Machado NG, Skildum AJ, Scott PM, Oliveira PJ. Mitochondrial remodeling in cancer metabolism and survival: potential for new therapies. Biochim Biophys Acta (2012) 1826:238-54. doi:10.1016/j.bbcan.2012.04.005
117. Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nat Rev Drug Discov (2010) 9:447-64. doi:10.1038/nrd3137