title: Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis.
abstract: A growing number of studies indicate that chronic stress can accelerate tumor growth due to sustained sympathetic nervous system activation. Our recent findings suggest that chronic stress is associated with increased IL8 levels. Here, we examined the molecular and biological significance of IL8 in stress-induced tumor growth. Norepinephrine (NE) treatment of ovarian cancer cells resulted in a 250-300% increase in IL8 protein and 240-320% increase in its mRNA levels. Epinephrine treatment resulted in similar increases. Moreover, NE treatment resulted in a 3.5-4-fold increase in IL8 promoter activity. These effects were blocked by propranolol. Promoter deletion analyses suggested that AP1 transcription factors might mediate catecholamine-stimulated up-regulation of IL8. siRNA inhibition studies identified FosB as the pivotal component responsible for IL8 regulation by NE. In vivo chronic stress resulted in increased tumor growth (by 221 and 235%; p < 0.01) in orthotopic xenograft models involving SKOV3ip1 and HeyA8 ovarian carcinoma cells. This enhanced tumor growth was completely blocked by IL8 or FosB gene silencing using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoliposomes. IL8 and FosB silencing reduced microvessel density (based on CD31 staining) by 2.5- and 3.5-fold, respectively (p < 0.001). Our findings indicate that neurobehavioral stress leads to FosB-driven increases in IL8, which is associated with increased tumor growth and metastases. These findings may have implications for ovarian cancer management.
authors.affiliation: Department of Gynecologic Oncology, RNA, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Jesusa M
authors.initials: JM
authors.lastname: Arevalo
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Myrthala
authors.initials: M
authors.lastname: Moreno-Smith
authors.forename: Masato
authors.initials: M
authors.lastname: Nishimura
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.forename: Pablo
authors.initials: P
authors.lastname: Vivas-Mejia
authors.forename: Susan K
authors.initials: SK
authors.lastname: Lutgendorf
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Steven W
authors.initials: SW
authors.lastname: Cole
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012149:Restraint, Physical / Q000523:psychology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C064269:FOSB protein, human; D016209:Interleukin-8; D016760:Proto-Oncogene Proteins c-fos; D014662:Vasoconstrictor Agents; D009638:Norepinephrine
references.citation: Clin Cancer Res. 2006 Jan 15;12(2):369-75
references.pmid: 16428474
references.citation: Oncogene. 2001 Apr 30;20(19):2401-12
references.pmid: 11402336
references.citation: Psychosom Med. 2000 May-Jun;62(3):337-45
references.pmid: 10845347
references.citation: J Natl Cancer Inst. 1998 Jan 7;90(1):30-6
references.pmid: 9428780
references.citation: Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129-57
references.pmid: 1751545
references.citation: Mol Cancer Ther. 2003 Aug;2(8):753-63
references.pmid: 12939465
references.citation: Oncol Res. 2000;12(2):97-106
references.pmid: 11132928
references.citation: Am J Obstet Gynecol. 2008 Apr;198(4):477.e1-9; discussion 477.e9-10
references.pmid: 18395047
references.citation: Histol Histopathol. 2000 Jul;15(3):921-8
references.pmid: 10963134
references.citation: J Natl Cancer Inst Monogr. 2001;(28):10-4
references.pmid: 11158201
references.citation: J Natl Cancer Inst. 2009 Sep 2;101(17):1193-205
references.pmid: 19641174
references.citation: Nature. 1988 Aug 18;334(6183):629-31
references.pmid: 2457172
references.citation: Arch Gen Psychiatry. 2003 Jan;60(1):100-3
references.pmid: 12511177
references.citation: Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8
references.pmid: 12516034
references.citation: Am J Pathol. 2008 Dec;173(6):1839-52
references.pmid: 18988806
references.citation: J Natl Cancer Inst. 2008 Mar 5;100(5):359-72
references.pmid: 18314475
references.citation: J Immunol. 2003 Mar 15;170(6):3369-76
references.pmid: 12626597
references.citation: J Cancer Res Clin Oncol. 1990;116(3):303-6
references.pmid: 2164516
references.citation: Ann Behav Med. 2000 Winter;22(1):29-37
references.pmid: 10892526
references.citation: Cancer. 2005 Jul 15;104(2):305-13
references.pmid: 15954082
references.citation: J Biol Chem. 2004 Oct 22;279(43):44889-96
references.pmid: 15302884
references.citation: Dev Comp Immunol. 1999 Jan-Feb;23(1):87-96
references.pmid: 10220071
references.citation: Brain Behav Immun. 2009 Feb;23(2):176-83
references.pmid: 18550328
references.citation: Clin Cancer Res. 2003 Oct 1;9(12):4514-21
references.pmid: 14555525
references.citation: Cancer Res. 2001 Apr 1;61(7):2866-9
references.pmid: 11306460
references.citation: Pharmacol Res. 1996 Apr-May;33(4-5):255-60
references.pmid: 8938018
references.citation: Nat Med. 2006 Aug;12(8):939-44
references.pmid: 16862152
references.citation: Int J Cancer. 2006 Jun 1;118(11):2744-9
references.pmid: 16381019
references.citation: Gynecol Oncol. 2006 Aug;102(2):244-51
references.pmid: 16434085
references.citation: J Steroid Biochem Mol Biol. 1991 Mar;38(3):307-20
references.pmid: 1848992
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: Oncogene. 2001 Apr 30;20(19):2390-400
references.pmid: 11402335
references.citation: J Natl Cancer Inst. 1998 Mar 18;90(6):447-54
references.pmid: 9521169
references.citation: Cell. 1996 Jul 26;86(2):297-309
references.pmid: 8706134
references.citation: Clin Biochem. 2004 May;37(5):363-9
references.pmid: 15087251
references.citation: Oncogene. 2001 Apr 30;20(19):2453-64
references.pmid: 11402340
references.citation: Clin Cancer Res. 2006 Aug 15;12(16):4916-24
references.pmid: 16914580
references.citation: Cancer Res. 2005 Aug 1;65(15):6910-8
references.pmid: 16061675
references.citation: Clin Cancer Res. 2005 Jul 1;11(13):4923-33
references.pmid: 16000591
references.citation: J Clin Oncol. 2005 Oct 1;23(28):7105-13
references.pmid: 16192594
references.citation: Clin Cancer Res. 2003 Jul;9(7):2786-97
references.pmid: 12855659
references.citation: Am J Pathol. 1997 Oct;151(4):1105-13
references.pmid: 9327744
references.citation: Cytokine Growth Factor Rev. 2001 Dec;12(4):375-91
references.pmid: 11544106
references.citation: Angiogenesis. 2005;8(1):63-71
references.pmid: 16132619
references.citation: Science. 1992 Dec 11;258(5089):1798-801
references.pmid: 1281554
references.citation: Nat Rev Cancer. 2002 May;2(5):383-9
references.pmid: 12044014
references.citation: Cancer. 2002 Jan 1;94(1):131-40
references.pmid: 11815969
references.citation: Neoplasia. 2001 Jan-Feb;3(1):33-42
references.pmid: 11326314
references.citation: Breast Cancer Res Treat. 2003 Jul;80(1):63-70
references.pmid: 12889599
references.citation: J Clin Oncol. 2004 Sep 1;22(17):3570-80
references.pmid: 15337807
references.citation: J Gerontol A Biol Sci Med Sci. 2001 Aug;56(8):M477-82
references.pmid: 11487599
references.citation: Int J Cancer. 2004 Nov 1;112(2):231-8
references.pmid: 15352035
references.citation: J Cell Biol. 2003 Feb 17;160(4):487-93
references.pmid: 12578910