title: Stat3 inhibitor Stattic exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia, Africa and Alaska. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin and radiotherapy. Signal transducer and activator of transcription 3 (Stat3) has been implicated in the development and progression of various solid tumors. In this study, we assessed the activation and expression of Stat3 in NPC cells. We found that Stat3 was activated and could be blocked by the small molecule inhibitor Stattic. The inhibition of Stat3 in NPC cells by Stattic decreased the expression of cyclin D1 in a dose- and time-dependent manner. Thus, Stattic was used to target Stat3 in NPC cell lines. We found that Stattic could inhibit cell viability and proliferation in NPC cells and significantly induced apoptosis. Additionally, Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of Stattic upon cell viability inhibition and apoptosis induction. Furthermore, Stattic sensitized NPC cells to cisplatin and ionizing radiation (IR) by preventing cell proliferation and inducing apoptosis. Taken together, Stattic inhibit Stat3 and display antitumor effect in NPC, and enhanced chemosensitivity and radiosensitivity in NPC. Therefore, our findings provide the base for more rational approaches to treat NPC in the clinic.
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Yunbao
authors: Y
authors: Pan
authors: Fuling
authors: F
authors: Zhou
authors: Ronghua
authors: R
authors: Zhang
authors: Francois X
authors: FX
authors: Claret
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D003499:Cyclic S-Oxides; D015850:Interleukin-6; D011838:Radiation-Sensitizing Agents; D050796:STAT3 Transcription Factor; C517409:stattic; D002945:Cisplatin
references: Eur J Cancer. 2010 Nov;46(16):2996-3006
references: 20709526
references: Science. 1994 Apr 1;264(5155):95-8
references: 8140422
references: Cancer Lett. 2012 Feb 28;315(2):198-205
references: 22104727
references: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
references: 17463090
references: Radiother Oncol. 2009 Sep;92(3):339-44
references: 19616333
references: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4700-5
references: 15781862
references: Oncogene. 2013 May 30;32(22):2756-66
references: 22797071
references: Breast Cancer Res. 2011 Jun 20;13(3):R65
references: 21689417
references: Clin Cancer Res. 2005 Nov 15;11(22):8131-44
references: 16299246
references: Cancer Lett. 2007 Jun 28;251(2):199-210
references: 17129668
references: Nature. 1998 Jul 9;394(6689):145-51
references: 9671298
references: Blood. 2011 May 26;117(21):5701-9
references: 21447830
references: Br J Cancer. 2003 Jul 21;89(2):344-9
references: 12865928
references: Nature. 1994 Sep 22;371(6495):346-7
references: 8090205
references: Int J Cancer. 2009 Oct 15;125(8):1884-93
references: 19588483
references: Mol Cell Biol. 1997 Aug;17(8):4677-86
references: 9234724
references: Oncogene. 2002 Oct 31;21(50):7611-8
references: 12400004
references: Oral Oncol. 2012 Dec;48(12):1220-6
references: 22770899
references: Semin Cancer Biol. 2012 Apr;22(2):79-86
references: 22245473
references: Cancer Res. 2011 Dec 1;71(23):7226-37
references: 21900397
references: J Virol. 2003 Apr;77(7):4139-48
references: 12634372
references: Oncogene. 2000 May 15;19(21):2607-11
references: 10851059
references: Ann Oncol. 2010 Oct;21 Suppl 7:vii308-12
references: 20943634
references: Oncogene. 2012 May 3;31(18):2309-22
references: 21909139
references: Cancer Cell. 2004 May;5(5):423-8
references: 15144950
references: Drug Resist Updat. 2010 Jun;13(3):67-78
references: 20471303
references: Clin Cancer Res. 2002 Apr;8(4):945-54
references: 11948098
references: Chem Biol. 2006 Nov;13(11):1235-42
references: 17114005
references: PLoS One. 2009;4(3):e4783
references: 19274102
references: Cancer Res. 2012 Apr 1;72(7):1890-900
references: 22350412
references: Lancet. 2005 Jun 11-17;365(9476):2041-54
references: 15950718
references: J Clin Oncol. 2009 Jan 10;27(2):242-9
references: 19064973
references: Int J Oncol. 2012 Oct;41(4):1181-91
references: 22842992
references: Nat Rev Cancer. 2004 Feb;4(2):97-105
references: 14964307
references: Cancer Lett. 2012 Dec 1;325(1):80-8
references: 22743617
references: Expert Opin Investig Drugs. 2009 Jan;18(1):45-56
references: 19053881
references: Cancer Lett. 2012 Jul 28;320(2):158-70
references: 22406826
references: Nature. 1995 Jul 6;376(6535):37-43
references: 7596430
references: Cancer Lett. 2012 Dec 30;326(2):155-60
references: 22867945
references: Nat Med. 2004 Jan;10(1):48-54
references: 14702634
references: Eur J Cancer. 2003 Oct;39(15):2121-35
references: 14522369