Dataset Information

Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization.

ABSTRACT: Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent TPA was established to study the prophylactic effect of DADS. As a result, we observed that DADS dose-dependently attenuated skin tumor incidence and multiplicity in the model mice, which was related to the up-regulation of a bunch of antioxidant enzymes activities and the nuclear accumulation of Nrf2. Furthermore, we developed skin carcinogenesis in Nrf2 knockout mice which could reverse the activity of DADS. Finally, we uncovered the underlying mechanism that DADS promoted the endogenous interaction between p21 and Nrf2, which was critical for impairing the Keap1-mediated degradation of Nrf2. Based on the results, we concluded that DADS was a promising cancer chemoprevention agent and suggested a garlic-rich diet might be beneficial to reduce the cancer risk in our daily life.

SUBMITTER: Shan Y

PROVIDER: S-EPMC5069634 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization.

Shan Yunlong Y Wei Zhonghong Z Tao Li L Wang Siliang S Zhang Feng F Shen Cunsi C Wu Hongyan H Liu Zhaoguo Z Zhu Pingting P Wang Aiyun A Chen Wenxing W Lu Yin Y

Scientific reports 20161019

Cancer prevention through intake of biologically active natural products appears to be an accessible way to reduce the risk of cancer. Diallyl disulfide (DADS), a major garlic derivative, has exhibited potential role in cancer therapy. The study is aimed to evaluate the prophylactic effect of DADS in chemically induced mouse skin carcinogenesis and investigate the molecular targets mediated by DADS. Two-stage chemically induced carcinogenesis model by cutaneous application of DMBA and subsequent ...[more]

PMID: 27759091

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Project description:The incidence of carcinoma increases greatly with aging, but the cellular and molecular mechanisms underlying this correlation are only partly known. It is established that senescent fibroblasts promote the malignant progression of already-transformed cells through secretion of inflammatory mediators. We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes. The physiopathological relevance of these results was tested by analyzing MMP activity and PAR-1 expression in skin sections. Both were higher in skin sections from aged subjects than in ones from young subjects. Altogether, our results suggest that during aging, the dermal and epidermal skin compartments might be activated coordinately for initiation of skin carcinoma, via a paracrine axis in which MMPs secreted by senescent fibroblasts promote very early epithelial-mesenchymal transition of keratinocytes undergoing transformation and oversynthesizing the MMP-activatable receptor PAR-1.

Dataset Information

Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization.

Publications

Prophylaxis of Diallyl Disulfide on Skin Carcinogenic Model via p21-dependent Nrf2 stabilization.

Similar Datasets

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