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


RESULTS
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
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.
Department of Urology, University of Texas Health Science Center, San Antonio, Texas, United States of America.
John P
JP
Fitzgerald
Bijaya
B
Nayak
Karthigayan
K
Shanmugasundaram
William
W
Friedrichs
Sunil
S
Sudarshan
Assaad A
AA
Eid
Thomas
T
DeNapoli
Dipen J
DJ
Parekh
Yves
Y
Gorin
Karen
K
Block
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D012265:Ribonucleotides / Q000494:pharmacology
D000975:Antioxidants; D015850:Interleukin-6; D016209:Interleukin-8; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide