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Supplementary Figures 1-3 from Crucial Role of Phospholipase Cε in Skin Inflammation Induced by Tumor-Promoting Phorbol Ester

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posted on 2023-03-30, 17:42 authored by Shuzo Ikuta, Hironori Edamatsu, Mingzhen Li, Lizhi Hu, Tohru Kataoka
Supplementary Figures 1-3 from Crucial Role of Phospholipase Cε in Skin Inflammation Induced by Tumor-Promoting Phorbol Ester

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ARTICLE ABSTRACT

In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase Cε (PLCε−/− mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLCε−/− mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLCε in tumor promotion. Here, we show that PLCε−/− mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1α (IL-1α). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLCε background, suggesting that the PLCε's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLCε lipase activity, which leads to the induction of IL-1α expression. Experiments using small interfering RNA–mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLCε is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLCε. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLCε activation, leading to tumor promotion. [Cancer Res 2008;68(1):64–72]

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