Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production

John P. Fitzgerald, Bijaya Nayak, Karthigayan Shanmugasundaram, William Friedrichs, Sunil Sudarshan, Assaad A. Eid, Thomas DeNapoli, Dipen J. Parekh, Yves Gorin, Karen Block

Research output: Contribution to journalArticle

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Abstract

Background: Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated. Methods and Principal Findings: We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion. Conclusions/Significance: Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC.

Original languageEnglish (US)
Article numbere30712
JournalPLoS One
Volume7
Issue number1
DOIs
StatePublished - Jan 27 2012

Fingerprint

cell invasion
interleukin-8
kidney cells
AMP-Activated Protein Kinases
Interleukin-8
Renal Cell Carcinoma
interleukin-6
carcinoma
hypoxia
Interleukin-6
Cells
AMP-activated protein kinase
Cytokines
cytokines
inflammation
Chemical activation
Inflammation
Hypoxia-Inducible Factor 1
Oxidative stress
NADPH Oxidase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fitzgerald, J. P., Nayak, B., Shanmugasundaram, K., Friedrichs, W., Sudarshan, S., Eid, A. A., ... Block, K. (2012). Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. PLoS One, 7(1), [e30712]. https://doi.org/10.1371/journal.pone.0030712

Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. / Fitzgerald, John P.; Nayak, Bijaya; Shanmugasundaram, Karthigayan; Friedrichs, William; Sudarshan, Sunil; Eid, Assaad A.; DeNapoli, Thomas; Parekh, Dipen J.; Gorin, Yves; Block, Karen.

In: PLoS One, Vol. 7, No. 1, e30712, 27.01.2012.

Research output: Contribution to journalArticle

Fitzgerald, JP, Nayak, B, Shanmugasundaram, K, Friedrichs, W, Sudarshan, S, Eid, AA, DeNapoli, T, Parekh, DJ, Gorin, Y & Block, K 2012, 'Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production', PLoS One, vol. 7, no. 1, e30712. https://doi.org/10.1371/journal.pone.0030712
Fitzgerald JP, Nayak B, Shanmugasundaram K, Friedrichs W, Sudarshan S, Eid AA et al. Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. PLoS One. 2012 Jan 27;7(1). e30712. https://doi.org/10.1371/journal.pone.0030712
Fitzgerald, John P. ; Nayak, Bijaya ; Shanmugasundaram, Karthigayan ; Friedrichs, William ; Sudarshan, Sunil ; Eid, Assaad A. ; DeNapoli, Thomas ; Parekh, Dipen J. ; Gorin, Yves ; Block, Karen. / Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. In: PLoS One. 2012 ; Vol. 7, No. 1.
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AU - Sudarshan, Sunil

AU - Eid, Assaad A.

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N2 - Background: Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated. Methods and Principal Findings: We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion. Conclusions/Significance: Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC.

AB - Background: Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated. Methods and Principal Findings: We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion. Conclusions/Significance: Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC.

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