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

• Published in: The Journal of biological chemistry Vol. 285; no. 46; pp. 35462 - 35470
• Main Authors: 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., Bottsford-Miller, Justin, Vivas-Mejia, Pablo, Lutgendorf, Susan K., Lopez-Berestein, Gabriel, Bar-Eli, Menashe, Cole, Steven W., Sood, Anil K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.11.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Angiogenesis; Animals; AP1 Transcription Factor; Catecholamine; Cell Line, Tumor; Chronic Stress; Enzyme-Linked Immunosorbent Assay; Female; FosB; Gene Expression Regulation, Neoplastic - drug effects; Gene Regulation; Humans; IL-8; Immunohistochemistry; Interleukin; Interleukin-8 - genetics; Interleukin-8 - metabolism; Mice; Mice, Nude; Models, Biological; Neoplasm Metastasis; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neurotransmitters; Norepinephrine - pharmacology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Restraint, Physical - psychology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Stress, Psychological; Transplantation, Heterologous; Tumor Burden - drug effects; Tumor Metastases; Tumor Microenvironment; Tumor Promoter; Vasoconstrictor Agents - pharmacology; Angiogenesis; Neurotransmitters; Interleukin; AP1 Transcription Factor; Tumor Metastases; FosB; Tumor Promoter; Catecholamine; IL-8; Chronic Stress
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M110.109579

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.