title: Restoring KLF5 in esophageal squamous cell cancer cells activates the JNK pathway leading to apoptosis and reduced cell survival.
abstract: Esophageal cancer is the eighth most common cancer in the world and has an extremely dismal prognosis, with a 5-year survival of less than 20%. Current treatment options are limited, and thus identifying new molecular targets and pathways is critical to derive novel therapies. Worldwide, more than 90% of esophageal cancers are esophageal squamous cell cancer (ESCC). Previously, we identified that Krüppel-like factor 5 (KLF5), a key transcriptional regulator normally expressed in esophageal squamous epithelial cells, is lost in human ESCC. To examine the effects of restoring KLF5 in ESCC, we transduced the human ESCC cell lines TE7 and TE15, both of which lack KLF5 expression, with retrovirus to express KLF5 upon doxycycline induction. When KLF5 was induced, ESCC cells demonstrated increased apoptosis and decreased viability, with up-regulation of the proapoptotic factor BAX. Interestingly, c-Jun N-terminal kinase (JNK) signaling, an important upstream mediator of proapoptotic pathways including BAX, was also activated following KLF5 induction. KLF5 activation of JNK signaling was mediated by KLF5 transactivation of two key upstream regulators of the JNK pathway, ASK1 and MKK4, and inhibition of JNK blocked apoptosis and normalized cell survival following KLF5 induction. Thus, restoring KLF5 in ESCC cells promotes apoptosis and decreases cell survival in a JNK-dependent manner, providing a potential therapeutic target for human ESCC.
authors: Department of Medicine, Gastroenterology Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6144, USA.
authors: Rohinton S
authors: RS
authors: Tarapore
authors: Yizeng
authors: Y
authors: Yang
authors: Jonathan P
authors: JP
authors: Katz
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004790:Enzyme Induction; D004938:Esophageal Neoplasms; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D018307:Neoplasms, Squamous Cell; D015533:Transcriptional Activation; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D051028:bcl-2-Associated X Protein; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human
references: Cancer Res. 2011 Oct 15;71(20):6475-84
references: 21868761
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: Eur J Cell Biol. 2011 Jun-Jul;90(6-7):536-44
references: 21333379
references: Oncogene. 2007 May 14;26(22):3100-12
references: 17496909
references: Cell. 2000 Oct 13;103(2):239-52
references: 11057897
references: Physiol Rev. 2012 Apr;92(2):689-737
references: 22535895
references: Int J Cell Biol. 2012;2012:439587
references: 22654913
references: N Engl J Med. 2012 May 31;366(22):2074-84
references: 22646630
references: Curr Opin Cell Biol. 2003 Dec;15(6):725-31
references: 14644197
references: J Biol Chem. 2008 Jul 4;283(27):18812-20
references: 18450752
references: Apoptosis. 2002 Aug;7(4):321-8
references: 12101391
references: J Cancer Res Clin Oncol. 1993;119(8):441-9
references: 8509434
references: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9
references: 7644477
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: Semin Oncol. 2004 Aug;31(4):476-86
references: 15297940
references: Science. 2002 Dec 6;298(5600):1911-2
references: 12471242
references: Cancer Res. 2007 Sep 1;67(17):7996-8001
references: 17804709
references: J Biol Chem. 2004 Mar 26;279(13):12093-101
references: 14726538
references: Oncogene. 2008 Sep 1;27(38):5115-23
references: 18758480
references: Nat Genet. 2002 May;31(1):64-8
references: 11967538
references: Cell Cycle. 2012 Nov 1;11(21):4033-9
references: 22990386
references: J Biol Chem. 2003 Jan 17;278(3):2058-65
references: 12426317
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
references: 11717429
references: Mol Cell Biol. 2000 Mar;20(5):1713-22
references: 10669748
references: Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1784-92
references: 17395897
references: Cell Res. 2005 Jan;15(1):36-42
references: 15686625
references: EMBO J. 2004 Apr 21;23(8):1889-99
references: 15071501
references: Prostate. 2003 May 1;55(2):81-8
references: 12661032
references: Cancer Epidemiol Biomarkers Prev. 2010 Aug;19(8):1893-907
references: 20647400
references: Clin Cancer Res. 2005 Aug 15;11(16):6065-74
references: 16115952
references: Bioessays. 2007 Jun;29(6):549-57
references: 17508399
references: Mol Cell Biol. 1996 Sep;16(9):4961-71
references: 8756655
references: Curr Protoc Bioinformatics. 2008 Mar;Chapter 2:Unit 2.6
references: 18428685
references: Biochim Biophys Acta. 2011 Apr;1813(4):532-9
references: 21056595
references: Genes Dev. 2001 Jun 1;15(11):1419-26
references: 11390361
references: FASEB J. 2007 Feb;21(2):543-50
references: 17158781
references: Oncogene. 2002 Sep 26;21(43):6567-72
references: 12242654
references: N Engl J Med. 2003 Dec 4;349(23):2241-52
references: 14657432
references: Cancer Biol Ther. 2005 Nov;4(11):1216-21
references: 16357509
references: Nat Cell Biol. 2002 May;4(5):E131-6
references: 11988758
references: Nat Rev Cancer. 2009 Aug;9(8):537-49
references: 19629069
references: Cell Mol Life Sci. 2009 Aug;66(16):2691-706
references: 19448973
references: Mol Cell. 2006 Mar 3;21(5):701-10
references: 16507367
references: Biochim Biophys Acta. 2008 Jan;1784(1):76-93
references: 17964301
references: Oncogene. 2008 Oct 20;27(48):6245-51
references: 18931691
references: Cell Res. 2005 Feb;15(2):92-6
references: 15740636
references: Prog Mol Biol Transl Sci. 2012;106:145-69
references: 22340717