Evidence that peroxisome proliferator-activated receptor γ suppresses squamous carcinogenesis through anti-inflammatory signaling and regulation of the immune response.
Evidence that peroxisome proliferator-activated receptor γ suppresses squamous carcinogenesis through anti-inflammatory signaling and regulation of the immune response.
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有证据表明过氧化物酶体增殖物激活受体γ通过抗炎信号传导和免疫反应调节抑制鳞状细胞癌发生。
DOI：
10.1002/mc.23041
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发表时间：
2019
影响因子：
4.6
通讯作者：
Konger,RaymondL
中科院分区：
文献类型：
--
作者：
Ren,Lu;Konger,RaymondL
各种证据表明，过氧化物酶体增殖物激活受体（PPAR）γ激动剂可能是预防或治疗皮肤癌的潜在药理学靶点。特别是，最近的报告表明，PPARγ激活可能通过抑制肿瘤促进慢性炎症以及通过加强抗肿瘤免疫应答来发挥其至少部分抗肿瘤作用。这种活性被认为是通过与PPARγ的配体相互作用的独特模式发生的，该模式导致参与炎症和免疫调节信号传导的转录因子的反式阻遏。然而，目前的噻唑烷二酮（TZD）型PPARγ激动剂具有显著的安全性问题，限制了其作为预防或治疗选择的有效性。由于PPARγ的配体结合口袋相对较大，可以看到不同的配体组以不同的结合模式与PPARγ相互作用，导致部分激动剂活性和选择性PPARγ调节剂（SPPARγM）现象。这导致了配体的开发，这些配体被定制为提供所需的药理学活性，但缺乏与完全激动剂相关的一些负面副作用，例如目前使用的TZD型PPARγ激动剂。此外，有证据表明，目前被吹捧为非营养保健品的许多植物化学物质也具有PPARγ活性，这可能部分解释了它们的药理活性。我们建议，这些部分激动剂中的一种或多种，SPPARγMs，或推定的植物化学PPARγ配体可能被用作设计更有效的抗肿瘤PPARγ配体的起点，没有不良药理作用。
A variety of evidence suggests that peroxisome proliferator‐activated receptor (PPAR)γ agonists may represent a potential pharmacologic target in the prevention or treatment of skin cancer. In particular, recent reports suggest that PPARγ activation may exert at least some of its anti‐neoplastic effects through the suppression of tumor promoting chronic inflammation as well as by strengthening antitumor immune responses. This activity is thought to occur through a distinct mode of ligand interaction with PPARγ that causes transrepression of transcription factors that are involved in inflammatory and immunomodulatory signaling. However, current thiazolidinedione (TZD)‐type PPARγ agonists have significant safety concerns that limit their usefulness as a preventive or therapeutic option. Due to the relatively large ligand binding pocket of PPARγ, a diverse group of ligands can be seen to interact with distinct modes of binding to PPARγ, leading to the phenomenon of partial agonist activity and selective PPARγ modulators (SPPARγM). This has led to the development of ligands that are tailored to deliver desired pharmacologic activity, but lack some of the negative side effects associated with full agonists, such as the currently utilized TZD‐type PPARγ agonists. In addition, there is evidence that a number of phytochemicals that are currently being touted as antineoplastic nutraceuticals also possess PPARγ activity that may partially explain their pharmacologic activity. We propose that one or more of these partial agonists, SPPARγMs, or putative phytochemical PPARγ ligands could presumably be used as a starting point to design more efficacious anti‐neoplastic PPARγ ligands that lack adverse pharmacological effects.