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Mol Carcinog. 2017 Dec;56(12):2643-2662. doi: 10.1002/mc.22708. Epub 2017 Aug 30.

NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1α and p27Kip1 expression in malignant melanoma and other human tumors.

Author information

1
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
2
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
3
Pathology/Histotechnology Laboratory, Leidos Inc./Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland.
4
Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California.

Abstract

NADPH oxidase 5 (NOX5) generated reactive oxygen species (ROS) have been implicated in signaling cascades that regulate cancer cell proliferation. To evaluate and validate NOX5 expression in human tumors, we screened a broad range of tissue microarrays (TMAs), and report substantial overexpression of NOX5 in malignant melanoma and cancers of the prostate, breast, and ovary. In human UACC-257 melanoma cells that possesses high levels of functional endogenous NOX5, overexpression of NOX5 resulted in enhanced cell growth, increased numbers of BrdU positive cells, and increased γ-H2AX levels. Additionally, NOX5-overexpressing (stable and inducible) UACC-257 cells demonstrated increased normoxic HIF-1α expression and decreased p27Kip1 expression. Similarly, increased normoxic HIF-1α expression and decreased p27Kip1 expression were observed in stable NOX5-overexpressing clones of KARPAS 299 human lymphoma cells and in the human prostate cancer cell line, PC-3. Conversely, knockdown of endogenous NOX5 in UACC-257 cells resulted in decreased cell growth, decreased HIF-1α expression, and increased p27Kip1 expression. Likewise, in an additional human melanoma cell line, WM852, and in PC-3 cells, transient knockdown of endogenous NOX5 resulted in increased p27Kip1 and decreased HIF-1α expression. Knockdown of endogenous NOX5 in UACC-257 cells resulted in decreased Akt and GSK3β phosphorylation, signaling pathways known to modulate p27Kip1 levels. In summary, our findings suggest that NOX5 expression in human UACC-257 melanoma cells could contribute to cell proliferation due, in part, to the generation of high local concentrations of extracellular ROS that modulate multiple pathways that regulate HIF-1α and networks that signal through Akt/GSK3β/p27Kip1 .

KEYWORDS:

Akt/GSK3 signaling; DNA damage; NADPH oxidase; cell growth; reactive oxygen species (ROS); tumor microarray (TMA)

PMID:
28762556
PMCID:
PMC5675809
DOI:
10.1002/mc.22708
[Indexed for MEDLINE]
Free PMC Article

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