Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis.
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.
Shahzad
Mian M K
MM
Department of Gynecologic Oncology, RNA, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Arevalo
Jesusa M
JM
Armaiz-Pena
Guillermo N
GN
Lu
Chunhua
C
Stone
Rebecca L
RL
Moreno-Smith
Myrthala
M
Nishimura
Masato
M
Lee
Jeong-Won
JW
Jennings
Nicholas B
NB
Bottsford-Miller
Justin
J
Vivas-Mejia
Pablo
P
Lutgendorf
Susan K
SK
Lopez-Berestein
Gabriel
G
Bar-Eli
Menashe
M
Cole
Steven W
SW
Sood
Anil K
AK
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
C064269:FOSB protein, human; D016209:Interleukin-8; D016760:Proto-Oncogene Proteins c-fos; D014662:Vasoconstrictor Agents; D009638:Norepinephrine
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