NDLI: Stress Effects on FosB- and Interleukin-8 (IL8)-driven Ovarian Cancer Growth and Metastasis*

Content Provider	PubMed Central
Author	Shahzad, Mian M. K. Arevalo, Jesusa M. Armaiz-pena, Guillermo N. Lu, Chunhua Stone, Rebecca L. Moreno-smith, Myrthala Nishimura, Masato Lee, Jeong-won Jennings, Nicholas B. Justin, Bottsford-miller Pablo, Vivas-mejia Lutgendorf, Susan K. Gabriel, Lopez-berestein Menashe, Bar-eli Cole, Steven W. Sood, Anil K.
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.
Related Links	http://dx.doi.org/10.1074/jbc.m110.109579
Ending Page	35470
Page Count	9
Starting Page	35462
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	46
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-11-12
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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