Ingenol Mebutate Signals via PKC/MEK/ERK in Keratinocytes and Induces Interleukin Decoy Receptors IL1R2 and IL13RA2
Ingenol Mebutate Signals via PKC/MEK/ERK in Keratinocytes and Induces Interleukin Decoy Receptors IL1R2 and IL13RA2
复制标题
DOI：
10.1158/1535-7163.mct-15-0023-t
复制
发表时间：
2015-09-01
影响因子：
5.7
通讯作者：
Hofbauer, Guenther F. L.
中科院分区：
文献类型：
--
作者：
Freiberger, Sandra N.;Cheng, Phil F.;Hofbauer, Guenther F. L.
鳞状细胞癌（SCC）是第二种最常见的人类皮肤癌，也是皮肤癌相关死亡的第二大原因。最近，一种新的化合物巨大戟醇甲基丁酸酯被批准用于治疗光化性角化病，这是SCC的前体。由于作用机制知之甚少，我们进一步研究了巨大戟醇甲基丁酸酯诱导细胞死亡的机制。我们阐明了巨大戟醇甲基丁酸酯对原代角质形成细胞，患者来源的SCC细胞和SCC细胞系的直接影响。对巨大戟醇甲基丁酸酯处理的原代角质形成细胞和患者来源的SCC细胞进行转录谱分析，然后进行通路分析，以找到关键介质并鉴定作用机制。在细胞和人皮肤外植体中证实了所得途径的激活，并通过经处理的原代细胞的磷酸化筛选得到支持。这些途径的必要性通过抑制某些途径组分来证明。Ingenolmebutate抑制所有角质形成细胞衍生的细胞的活力和增殖的双相方式。转录谱鉴定了PKC/MEK/ERK信号传导参与作用机制，并且在用100 nmol/L巨大戟醇甲基丁酸酯（第一响应峰的最佳浓度）处理后抑制该信号传导途径拯救了巨大戟醇甲基丁酸酯诱导的细胞死亡。我们发现巨大戟醇甲基丁酸酯以PKC/MEK/ERK依赖的方式诱导白细胞介素诱饵受体IL 1 R2和IL 13 RA 2。此外，IL 1 R2和IL 13 RA 2的siRNA敲低部分拯救了巨大戟醇甲基丁酸盐处理的细胞。总之，我们已经表明巨大戟醇甲基丁酸酯诱导的细胞死亡是通过PKCd/MEK/ERK途径介导的，并且我们已经在功能上将IL 1 R2和IL 13 RA 2表达的下游诱导与巨大戟醇甲基丁酸酯处理的细胞的活力降低相关联。(C)2015年AACR。
Squamous cell carcinoma (SCC) is the second most common human skin cancer and the second leading cause of skin cancer-related death. Recently, a new compound, ingenol mebutate, was approved for treatment of actinic keratosis, a precursor of SCC. As the mechanism of action is poorly understood, we have further investigated the mechanism of ingenol mebutate-induced cell death. We elucidate direct effects of ingenol mebutate on primary keratinocytes, patient-derived SCC cells, and a SCC cell line. Transcriptional profiling followed by pathway analysis was performed on ingenol mebutate-treated primary keratinocytes and patient-derived SCC cells to find key mediators and identify the mechanism of action. Activation of the resulting pathways was confirmed in cells and human skin explants and supported by a phosphorylation screen of treated primary cells. The necessity of these pathways was demonstrated by inhibition of certain pathway components. Ingenolmebutate inhibited viability and proliferation of all keratinocyte-derived cells in a biphasic manner. Transcriptional profiling identified the involvement of PKC/MEK/ERK signaling in the mechanism of action and inhibition of this signaling pathway rescued ingenol mebutate-induced cell death after treatment with 100 nmol/L ingenol mebutate, the optimal concentration for the first peak of response. We found the interleukin decoy receptors IL1R2 and IL13RA2 induced by ingenol mebutate in a PKC/MEK/ERK-dependent manner. Furthermore, siRNA knockdown of IL1R2 and IL13RA2 partially rescued ingenol mebutate-treated cells. In conclusion, we have shown that ingenol mebutate-induced cell death is mediated through the PKCd/MEK/ERK pathway, and we have functionally linked the downstream induction of IL1R2 and IL13RA2 expression to the reduced viability of ingenol mebutate-treated cells. (C) 2015 AACR.