γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: Potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent

British Journal of Pharmacology

Volumn 163, Issue 2, 2011, Pages 283-298

  Rajendran, Peramaiyan ^a   Li, Feng ^a   Manu, Kanjoormana Aryan ^a   Shanmugam, Muthu K ^a   Loo, Ser Yue ^a,b   Kumar, Alan Prem ^a,b   Sethi, Gautam ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

tocotrienol; apoptosis; hepatocellular carcinoma; JAK2; proliferation; STAT3

Indexed keywords

CYCLIN D1; DOXORUBICIN; GAMMA TOCOTRIENOL; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; JANUS KINASE 1; JANUS KINASE 2; PACLITAXEL; PHOSPHOPROTEIN PHOSPHATASE; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN MCL 1; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE PHOSPHATASE SHP 1; STAT3 PROTEIN; SURVIVIN; VASCULOTROPIN;

ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CARCINOMA CELL; CELL PROLIFERATION; CELLULAR DISTRIBUTION; CHEMOSENSITIZATION; CONTROLLED STUDY; DOWN REGULATION; DRUG EFFECT; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; LIVER CELL CARCINOMA; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CARCINOMA, HEPATOCELLULAR; CELL LINE, TUMOR; CELL NUCLEUS; CELL PROLIFERATION; CHROMANS; DOXORUBICIN; DRUG RESISTANCE, NEOPLASM; DRUG SYNERGISM; ENZYME ACTIVATION; ENZYME INDUCTION; GENES, REPORTER; HUMANS; JANUS KINASES; LIVER NEOPLASMS; NF-KAPPA B; PACLITAXEL; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTEIN TYROSINE PHOSPHATASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; SRC-FAMILY KINASES; STAT3 TRANSCRIPTION FACTOR; VITAMIN E;

EID: 79954459349     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2010.01187.x     Document Type: Article

References (100)

1. Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, et al,. (2006). Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci 1091: 151-169. (Pubitemid 47092233)
2. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, et al,. (2009a). Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 1171: 59-76.
3. Aggarwal BB, Vijayalekshmi RV, Sung B, (2009b). Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15: 425-430.
4. Aggarwal BB, Sundaram C, Prasad S, Kannapan R, (2010). Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80: 1613-1631.
5. Ahn KS, Sethi G, Krishnan K, Aggarwal BB, (2007). Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 282: 809-820. (Pubitemid 47076658)
6. Avila MA, Berasain C, Sangro B, Prieto J, (2006). New therapies for hepatocellular carcinoma. Oncogene 25: 3866-3884. (Pubitemid 43980482)
7. Bachawal SV, Wali VB, Sylvester PW, (2010). Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res 30: 429-437.
8. Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA, (2009). Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci 1155: 206-221.
9. Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G, et al,. (2007). Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13: 3024-3032. (Pubitemid 46849579)
10. Bi S, Liu JR, Li Y, Wang Q, Liu H, Yan YG, et al,. (2010). gamma-Tocotrienol modulates the paracrine secretion of VEGF induced by cobalt(II) chloride via ERK signaling pathway in gastric adenocarcinoma SGC-7901 cell line. Toxicology 274: 27-33.
11. Brierley MM, Fish EN, (2005). Stats: multifaceted regulators of transcription. J Interferon Cytokine Res 25: 733-744. (Pubitemid 43071210)
12. Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al,. (2006). Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130: 1117-1128.
13. Campbell GS, Yu CL, Jove R, Carter-Su C, (1997). Constitutive activation of JAK1 in Src-transformed cells. J Biol Chem 272: 2591-2594. (Pubitemid 27053296)
14. Chang PN, Yap WN, Lee DT, Ling MT, Wong YC, Yap YL, (2009). Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. Nutr Cancer 61: 357-366.
15. Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML, (1999). Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 274: 23013-23019.
16. Chiarugi P, Cirri P, Marra F, Raugei G, Fiaschi T, Camici G, et al,. (1998). The Src and signal transducers and activators of transcription pathways as specific targets for low molecular weight phosphotyrosine-protein phosphatase in platelet-derived growth factor signaling. J Biol Chem 273: 6776-6785. (Pubitemid 28160340)
17. Choudhari SR, Khan MA, Harris G, Picker D, Jacob GS, Block T, et al,. (2007). Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod. Mol Cancer Ther 6: 112-121. (Pubitemid 46206673)
18. Chua AW, Hay HS, Rajendran P, Shanmugam MK, Li F, Bist P, et al,. (2010). Butein downregulates chemokine receptor CXCR4 expression and function through suppression of NF-kappaB activation in breast and pancreatic tumor cells. Biochem Pharmacol 80: 1553-1562.
19. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, et al,. (1997). Specific inhibition of Stat3 signal transduction by PIAS3. Science 278: 1803-1805. (Pubitemid 27527648)
20. Costantino L, Barlocco D, (2008). STAT 3 as a target for cancer drug discovery. Curr Med Chem 15: 834-843. (Pubitemid 351736406)
21. Devarajan E, Huang S, (2009). STAT3 as a central regulator of tumor metastases. Curr Mol Med 9: 626-633.
22. Digicaylioglu M, Lipton SA, (2001). Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412: 641-647. (Pubitemid 32772276)
23. Eitsuka T, Nakagawa K, Miyazawa T, (2006). Down-regulation of telomerase activity in DLD-1 human colorectal adenocarcinoma cells by tocotrienol. Biochem Biophys Res Commun 348: 170-175. (Pubitemid 44163497)
24. Elangovan S, Hsieh TC, Wu JM, (2008). Growth inhibition of human MDA-mB-231 breast cancer cells by delta-tocotrienol is associated with loss of cyclin D1/CDK4 expression and accompanying changes in the state of phosphorylation of the retinoblastoma tumor suppressor gene product. Anticancer Res 28: 2641-2647.
25. El-Serag HB, Rudolph KL, (2007). Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132: 2557-2576. (Pubitemid 46890874)
26. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, et al,. (1997). A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387: 921-924. (Pubitemid 27289595)
27. Epling-Burnette PK, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, et al,. (2001). Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 107: 351-362.
28. Fang F, Kang Z, Wong C, (2010). Vitamin E tocotrienols improve insulin sensitivity through activating peroxisome proliferator-activated receptors. Mol Nutr Food Res 54: 345-352.
29. Farazi PA, DePinho RA, (2006). Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6: 674-687. (Pubitemid 44286000)
30. Gao SP, Bromberg JF, (2006). Touched and moved by STAT3. Sci STKE 2006: pe30.
31. Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA, et al,. (2001). Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20: 2499-2513. (Pubitemid 32531347)
32. Gould MN, Haag JD, Kennan WS, Tanner MA, Elson CE, (1991). A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors. Am J Clin Nutr 53 (Suppl.): 1068S-1070S. (Pubitemid 21898877)
33. Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, et al,. (2006). Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12: 11-19. (Pubitemid 43166170)
34. Grivennikov SI, Karin M, (2010). Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21: 11-19.
35. Gunaje JJ, Bhat GJ, (2001). Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin. Biochem Biophys Res Commun 288: 252-257. (Pubitemid 32999754)
36. Han Y, Amin H, Franko B, Frantz C, Shi X, Lai R, (2006). Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK-positive anaplastic large-cell lymphoma. Blood 108: 2796-2803.
37. He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE, (1997). Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J Nutr 127: 668-674. (Pubitemid 27200738)
38. Hiura Y, Tachibana H, Arakawa R, Aoyama N, Okabe M, Sakai M, et al,. (2009). Specific accumulation of gamma- and delta-tocotrienols in tumor and their antitumor effect in vivo. J Nutr Biochem 20: 607-613.
39. Ihle JN, (1996). STATs: signal transducers and activators of transcription. Cell 84: 331-334. (Pubitemid 26058558)
40. Iqbal J, Minhajuddin M, Beg ZH, (2004). Suppression of diethylnitrosamine and 2-acetylaminofluorene-induced hepatocarcinogenesis in rats by tocotrienol-rich fraction isolated from rice bran oil. Eur J Cancer Prev 13: 515-520. (Pubitemid 39620257)
41. Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, et al,. (2001). CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409: 349-354. (Pubitemid 32151240)
42. Jin C, Li H, He Y, He M, Bai L, Cao Y, et al,. (2009). Combination chemotherapy of doxorubicin and paclitaxel for hepatocellular carcinoma in vitro and in vivo. J Cancer Res Clin Oncol 136: 267-274.
43. Kashiwagi K, Virgona N, Harada K, Kido W, Yano Y, Ando A, et al,. (2009). A redox-silent analogue of tocotrienol acts as a potential cytotoxic agent against human mesothelioma cells. Life Sci 84: 650-656.
44. Kern MA, Breuhahn K, Schirmacher P, (2002). Molecular pathogenesis of human hepatocellular carcinoma. Adv Cancer Res 86: 67-112.
45. Kerr SH, Kerr DJ, (2009). Novel treatments for hepatocellular cancer. Cancer Lett 286: 114-120.
46. Kim H, Baumann H, (1999). Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol Cell Biol 19: 5326-5338. (Pubitemid 29339892)
47. Kortylewski M, Feld F, Kruger KD, Bahrenberg G, Roth RA, Joost HG, et al,. (2003). Akt modulates STAT3-mediated gene expression through a FKHR (FOXO1a)-dependent mechanism. J Biol Chem 278: 5242-5249. (Pubitemid 36801037)
48. Kumar KS, Raghavan M, Hieber K, Ege C, Mog S, Parra N, et al,. (2006). Preferential radiation sensitization of prostate cancer in nude mice by nutraceutical antioxidant gamma-tocotrienol. Life Sci 78: 2099-2104.
49. Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey S, et al,. (2010). {Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment. Cancer Res 70: 8695-8705.
50. Kusaba M, Nakao K, Goto T, Nishimura D, Kawashimo H, Shibata H, et al,. (2007). Abrogation of constitutive STAT3 activity sensitizes human hepatoma cells to TRAIL-mediated apoptosis. J Hepatol 47: 546-555. (Pubitemid 47331746)
51. Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, et al,. (2009). Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15: 283-293.
52. Li F, Fernandez PP, Rajendran P, Hui KM, Sethi G, (2010a). Diosgenin, a steroidal saponin, inhibits STAT3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells. Cancer Lett 292: 197-207.
53. Li F, Tan W, Kang Z, Wong CW, (2010b). Tocotrienol enriched palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferators-activated receptors. Atherosclerosis 211: 278-282.
54. Li WC, Ye SL, Sun RX, Liu YK, Tang ZY, Kim Y, et al,. (2006). Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin Cancer Res 12: 7140-7148. (Pubitemid 44974515)
55. Lin L, Amin R, Gallicano GI, Glasgow E, Jogunoori W, Jessup JM, et al,. (2009). The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling. Oncogene 28: 961-972.
56. Liu HK, Wang Q, Li Y, Sun WG, Liu JR, Yang YM, et al,. (2010). Inhibitory effects of gamma-tocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 21: 206-213.
57. Liu P, Kimmoun E, Legrand A, Sauvanet A, Degott C, Lardeux B, et al,. (2002). Activation of NF-kappa B, AP-1 and STAT transcription factors is a frequent and early event in human hepatocellular carcinomas. J Hepatol 37: 63-71. (Pubitemid 34713056)
58. Lufei C, Koh TH, Uchida T, Cao X, (2007). Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. Oncogene 26: 7656-7664. (Pubitemid 350224213)
59. McAnally JA, Gupta J, Sodhani S, Bravo L, Mo H, (2007). Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. Exp Biol Med (Maywood) 232: 523-531. (Pubitemid 46524474)
60. Moran DM, Mattocks MA, Cahill PA, Koniaris LG, McKillop IH, (2008). Interleukin-6 mediates G(0)/G(1) growth arrest in hepatocellular carcinoma through a STAT 3-dependent pathway. J Surg Res 147: 23-33. (Pubitemid 351626069)
61. Newman DJ, (2008). Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J Med Chem 51: 2589-2599. (Pubitemid 351620778)
62. Ngah WZ, Jarien Z, San MM, Marzuki A, Top GM, Shamaan NA, et al,. (1991). Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats. Am J Clin Nutr 53 (Suppl.): 1076S-1081S. (Pubitemid 21898879)
63. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, et al,. (2002). Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21: 2000-2008. (Pubitemid 34270888)
64. Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, et al,. (2005). Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24: 6406-6417. (Pubitemid 41486474)
65. Park SK, Sanders BG, Kline K, (2010). Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 124: 361-375.
66. Pierpaoli E, Viola V, Pilolli F, Piroddi M, Galli F, Provinciali M, (2010). Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression. Life Sci 86: 668-675.
67. Rampone B, Schiavone B, Martino A, Viviano C, Confuorto G, (2009). Current management strategy of hepatocellular carcinoma. World J Gastroenterol 15: 3210-3216.
68. Sakai M, Okabe M, Yamasaki M, Tachibana H, Yamada K, (2004). Induction of apoptosis by tocotrienol in rat hepatoma dRLh-84 cells. Anticancer Res 24: 1683-1688. (Pubitemid 38954695)
69. Sakai M, Okabe M, Tachibana H, Yamada K, (2006). Apoptosis induction by gamma-tocotrienol in human hepatoma Hep3B cells. J Nutr Biochem 17: 672-676. (Pubitemid 44380370)
70. Samant GV, Sylvester PW, (2006). gamma-Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells. Cell Prolif 39: 563-574. (Pubitemid 44760206)
71. Samant GV, Wali VB, Sylvester PW, (2010). Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif 43: 77-83.
72. Schreiner SJ, Schiavone AP, Smithgall TE, (2002). Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. J Biol Chem 277: 45680-45687. (Pubitemid 36159180)
73. Seitz SJ, Schleithoff ES, Koch A, Schuster A, Teufel A, Staib F, et al,. (2009). Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway. Int J Cancer 126: 2049-2066.
74. Sen CK, Khanna S, Roy S, Packer L, (2000). Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem 275: 13049-13055. (Pubitemid 30241466)
75. Sen CK, Khanna S, Rink C, Roy S, (2007). Tocotrienols: the emerging face of natural vitamin E. Vitam Horm 76: 203-261.
76. Srivastava JK, Gupta S, (2006). Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochem Biophys Res Commun 346: 447-453. (Pubitemid 43902706)
77. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, et al,. (1997). A family of cytokine-inducible inhibitors of signalling. Nature 387: 917-921. (Pubitemid 27289594)
78. Sun S, Steinberg BM, (2002). PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells. J Gen Virol 83: 1651-1658. (Pubitemid 34716270)
79. Sun W, Wang Q, Chen B, Liu J, Liu H, Xu W, (2008). Gamma-tocotrienol- induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling. Br J Nutr 99: 1247-1254.
80. Sun W, Xu W, Liu H, Liu J, Wang Q, Zhou J, et al,. (2009). gamma-Tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 20: 276-284.
81. Sundram K, Khor HT, Ong AS, Pathmanathan R, (1989). Effect of dietary palm oils on mammary carcinogenesis in female rats induced by 7,12-dimethylbenz(a)anthracene. Cancer Res 49: 1447-1451. (Pubitemid 19088680)
82. Tan SM, Li F, Rajendran P, Prem Kumar A, Hui KM, Sethi G, (2010). Identification of {beta}-escin as a novel inhibitor of STAT3/JAK2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J Pharmacol Exp Ther 334: 285-293.
83. Tanuma N, Nakamura K, Shima H, Kikuchi K, (2000). Protein-tyrosine phosphatase PTPepsilon C inhibits Jak-STAT signaling and differentiation induced by interleukin-6 and leukemia inhibitory factor in M1 leukemia cells. J Biol Chem 275: 28216-28221.
84. Tatebe H, Shimizu M, Shirakami Y, Tsurumi H, Moriwaki H, (2008). Synergistic growth inhibition by 9-cis-retinoic acid plus trastuzumab in human hepatocellular carcinoma cells. Clin Cancer Res 14: 2806-2812.
85. Tenev T, Bohmer SA, Kaufmann R, Frese S, Bittorf T, Beckers T, et al,. (2000). Perinuclear localization of the protein-tyrosine phosphatase SHP-1 and inhibition of epidermal growth factor-stimulated STAT1/3 activation in A431 cells. Eur J Cell Biol 79: 261-271. (Pubitemid 30232571)
86. Wada S, Satomi Y, Murakoshi M, Noguchi N, Yoshikawa T, Nishino H, (2005). Tumor suppressive effects of tocotrienol in vivo and in vitro. Cancer Lett 229: 181-191. (Pubitemid 41429357)
87. Waris G, Turkson J, Hassanein T, Siddiqui A, (2005). Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress: role of STAT-3 in HCV replication. J Virol 79: 1569-1580. (Pubitemid 40459104)
88. Weng-Yew W, Selvaduray KR, Ming CH, Nesaretnam K, (2009). Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis. Nutr Cancer 61: 367-373.
89. Woetmann A, Nielsen M, Christensen ST, Brockdorff J, Kaltoft K, Engel AM, et al,. (1999). Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3. Proc Natl Acad Sci U S A 96: 10620-10625. (Pubitemid 29442193)
90. Wu C, Guan Q, Wang Y, Zhao ZJ, Zhou GW, (2003). SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases. J Cell Biochem 90: 1026-1037. (Pubitemid 37467118)
91. Xu WL, Liu JR, Liu HK, Qi GY, Sun XR, Sun WG, et al,. (2009). Inhibition of proliferation and induction of apoptosis by gamma-tocotrienol in human colon carcinoma HT-29 cells. Nutrition 25: 555-566.
92. Yamamoto T, Sekine Y, Kashima K, Kubota A, Sato N, Aoki N, et al,. (2002). The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation. Biochem Biophys Res Commun 297: 811-817. (Pubitemid 35230323)
93. Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, et al,. (2008). Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer 99: 1832-1841.
94. Yap WN, Zaiden N, Luk SY, Lee DT, Ling MT, Wong YC, et al,. (2010a). In vivo evidence of gamma-tocotrienol as a chemosensitizer in the treatment of hormone-refractory prostate cancer. Pharmacology 85: 248-258.
95. Yap WN, Zaiden N, Tan YL, Ngoh CP, Zhang XW, Wong YC, et al,. (2010b). Id1, inhibitor of differentiation, is a key protein mediating anti-tumor responses of gamma-tocotrienol in breast cancer cells. Cancer Lett 291: 187-199.
96. Yoshida T, Hanada T, Tokuhisa T, Kosai K, Sata M, Kohara M, et al,. (2002). Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 196: 641-653. (Pubitemid 35024442)
97. Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, et al,. (2001). SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28: 29-35. (Pubitemid 32405812)
98. Yu H, Pardoll D, Jove R, (2009). STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9: 798-809.
99. Yue P, Turkson J, (2009). Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs 18: 45-56.
100. Zhang Q, Raghunath PN, Xue L, Majewski M, Carpentieri DF, Odum N, et al,. (2002). Multilevel dysregulation of STAT3 activation in anaplastic lymphoma kinase-positive T/null-cell lymphoma. J Immunol 168: 466-474. (Pubitemid 34014150)