Inhibition of NADPH oxidase 1 activity and blocking the binding of cytosolic and membrane-bound proteins by honokiol inhibit migratory potential of melanoma cells
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Ram Prasad1, John C. Kappes2,5,6, Santosh K. Katiyar1,3,4,5,6
1Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
2Departments of Medicine and Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
3Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
4Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA
5Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
6Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
Santosh K. Katiyar, e-mail: [email protected]
Keywords: honokiol, melanoma, NADPH oxidase, cell migration, imaging
Received: September 07, 2015 Accepted: January 02, 2016 Published: January 09, 2016
Overexpression of NADPH oxidase 1 (Nox1) in melanoma cells is often associated with increased migration/metastasis rate. To develop effective treatment options, we have examined the effect of honokiol, a phytochemical from Magnolia plant, on the migratory potential of human melanoma cell lines (A375, Hs294t, SK-Mel119 and SK-Mel28) and assessed whether Nox1 is the target. Using an in vitro cell migration assay, we observed that treatment of different melanoma cell lines with honokiol for 24 h resulted in a dose-dependent inhibition of cell migration that was associated with reduction in Nox1 expression and reduced levels of oxidative stress. Treatment of cells with N-acetyl-L-cysteine, an anti-oxidant, also inhibited the migration of melanoma cells. Treatment of cells with diphenyleneiodonium chloride, an inhibitor of Nox1, significantly decreased the migration ability of Hs294t and SK-Mel28 cells. Further, we examined the effect of honokiol on the levels of core proteins (p22phox and p47phox) of the NADPH oxidase complex. Treatment of Hs294t and SK-Mel28 cells with honokiol resulted in accumulation of the cytosolic p47phox protein and decreased levels of the membrane-bound p22phox protein, thus blocking their interaction and inhibiting Nox1 activation. Our in vivo bioluminescence imaging data indicate that oral administration of honokiol inhibited the migration/extravasation and growth of intravenously injected melanoma cells in internal body organs, such as liver, lung and kidney in nude mice, and that this was associated with an inhibitory effect on Nox1 activity in these internal organs/tissues.
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