NADPH Oxidases as Novel Targets for Cancer Therapy

Division Of Basic Sciences - Nci

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Abstract

During the current funding period, we have made major progress in understanding the mechanisms by which pro-inflammatory cytokines upregulate DUOX2 and NOX1 and the effect of HDACs on NOX5 expression. In pancreatic cancer cells and xenografts, DUOX2 plays a critical role in tumor cell proliferation, as demonstrated by CRISPR knockout experiments. We also found that the essential features of DUOX2 regulation are produced by JAK/Stat signaling across a variety of cytokines. For colon cancer cells, Stat1 and Stat3 work synergistically to enhance DUOX2 expression after exposure to IL1 and IL6. We also found that there is a remarkable multi-cytokine synergy amongst TNF alpha, IL-22, and IL-6 that dramatically upregulates DUOX2 and associated hydrogen peroxide production in human colon cancer cells, leading to tumor cell necrosis. In melanoma cell lines, HDAC inhibitors markedly enhance the expression of NOX5 through the combined effects of SP1 and SP3 as well as Brd4 on the NOX5 promoter. The dramatic increase in superoxide produced by HDACi's also affects cell growth, as expected.