Tumor promoter-induced sulfiredoxin is required for mouse skin tumorigenesis

Abstract

Sulfiredoxin (Srx), the exclusive enzyme that reduces the hyperoxidized inactive form of peroxiredoxins (Prxs), has been found highly expressed in several types of human skin cancer. To determine whether Srx contributed to skin tumorigenesis in vivo, Srx null mice were generated on an FVB background. Mouse skin tumorigenesis was induced by a 7,12-dimethylbenz[α]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) protocol. We found that the number, volume and size of papillomas in Srx(-/-) mice were significantly fewer compared with either wild-type (Wt) or heterozygous (Het) siblings. Histopathological analysis revealed more apoptotic cells in tumors from Srx(-/-) mice. Mechanistic studies in cell culture revealed that Srx was stimulated by TPA in a redox-independent manner. This effect was mediated transcriptionally through the activation of mitogen-activated protein kinase and Jun-N-terminal kinase. We also demonstrated that Srx was capable of reducing hyperoxidized Prxs to facilitate cell survival under oxidative stress conditions. These findings suggested that loss of Srx protected mice, at least partially, from DMBA/TPA-induced skin tumorigenesis. Therefore, Srx has an oncogenic role in skin tumorigenesis and targeting Srx may provide novel strategies for skin cancer prevention or treatment.

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

“…Another study from Wei et al demonstrated high SRXN1 protein expression in human colon carcinoma and showed that Srxn1 knockout animals were resistant to carcinogenic induction [76]. In addition, SRXN1 expression is increased in different human skin malignancies [77,78] and gastric cancer [79].…”

Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage

“…The initial correlation of Srx to cancer emerged from its differential expression in the transformation-sensitive mouse JB6 epidermal cells [36]. It was further demonstrated that Srx is overexpressed in cancers of skin, lung, and rectum, but not in normal tissues, and has an oncogenic role in promoter-induced tumorigenesis of skin and colon, and in lung cancer cells [24][25][26]37,38], indicating that Srx might be targeted for cancer prevention or treatment. Here, we showed that the inhibition of Srx activity in human lung adenocarcinoma A549 cells causes oxidative stress, which in turn leads to mitochondrial damage resulting in apoptotic cell death.…”

The sulfiredoxin–peroxiredoxin (Srx–Prx) axis in cell signal transduction and cancer development

“…Srx protein is also over-expressed in renal cell carcinoma where it is proposed to be a good antibody target that can result in tumor cell death [74]. Srx expression is stimulated by TPA via MAPK/JNK ( c-Jun N-terminal kinase ) pathway in skin carcinogenesis and Srx depletion at least partially protects mice against DMBA( 7,12-dimethylbenz[a]anthracene )/TPA-induced skin carcinogenesis [75]. Srx is also necessary for colon carcinogenesis as it is highly over-expressed in colon tumor tissue compared to normal human colon, and Srx null mice are highly resistant to azoxymethane/dextran sulfate sodium -induced colon carcinogenesis [33].…”