Dual Role of the Antioxidant Enzyme Peroxiredoxin 6 in Skin Carcinogenesis

Abstract

The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8-induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis. Cancer Res; 73(11); 3460-9. Ó2013 AACR.

Cancer, Oxidative Stress, and Metastasis

“…Prdx6 overexpression in keratinocytes can reduce the initiation of skin tumors, but once they arise, cancer progression is accelerated by Prdx6 overexpression (Rolfs et al 2013). Similarly, NRF2 confers resistance to chemical carcinogens but also promotes cancer progression by protecting cancer cells from oxidative stress and DNA damage (Ramos-Gomez et al 2001;Iida et al 2004;Hayes and McMahon 2006;Hu et al 2006;Xu et al 2006;Ma 2013;Satoh et al 2013).…”

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

“…BrdU labeling was performed by incubation of cultured cells in 100 mM BrdU (Roche, Rotkreuz, Switzerland) for 2 h. Cells were fixed with 4% paraformaldehyde, and BrdU was detected by immunofluorescence analysis, as described previously (11).…”

Proteomic Characterization of Plasma Cells from Patients with Multiple Myeloma

“…hnRNP M plays role in mediating metastasis and the inflammatory response [76,77], while under-expression of peroxidoxin-6 enhances the susceptibility of cells to tumorigenesis [78]. Isoform 1 of myosin-9 is a known binding protein that binds to a number of proteins related to cancer progression and the unconventional secretory pathway [79].…”