Tsuchida Tomoki, Uehara Takashi
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University.
Nihon Yakurigaku Zasshi. 2022;157(5):352-355. doi: 10.1254/fpj.22043.
The epidermal growth factor receptor (EGFR) is the most extensively examined receptor tyrosine kinase. Several EGFR mutations and modifications have been shown to induce self-activation, which plays a central role in carcinogenesis. Recently, environmental chemicals such as PM2.5 can also activate EGFR and become risk factors for cancer. Although, the detailed mechanism remains unknown. In this study, we focused on 1,2-naphthoquinone (1,2-NQ) which is a secondary metabolite of naphthalene. Humans are exposed to 1,2-NQ through the combustion of fossil and diesel fuel and from tobacco smoke and PM2.5. Here, we demonstrate that 1,2-NQ is a novel EGFR-specific activator. We found that 1,2-NQ forms a covalent bond called N-arylation with EGFR Lys80 which is in the extracellular domain by LC-MS/MS. This modification activates the EGFR-Akt signaling pathway, which inhibits serum deprivation-induced apoptosis in A549 cells. Our study reveals an original mode of EGFR activation via covalent binding. We propose the correlation between EGFR activation without ligands and environmental pollutant-associated diseases such as cancer.
表皮生长因子受体（EGFR）是研究最为广泛的受体酪氨酸激酶。已证实多种EGFR突变和修饰可诱导自身激活，这在致癌过程中起着核心作用。最近，诸如PM2.5等环境化学物质也能激活EGFR并成为癌症的危险因素。不过，具体机制仍不明晰。在本研究中，我们聚焦于1,2 - 萘醌（1,2 - NQ），它是萘的一种次级代谢产物。人类通过化石燃料和柴油的燃烧、烟草烟雾以及PM2.5接触到1,2 - NQ。在此，我们证明1,2 - NQ是一种新型的EGFR特异性激活剂。我们通过液相色谱 - 串联质谱法（LC - MS/MS）发现，1,2 - NQ与位于细胞外结构域的EGFR赖氨酸80形成一种名为N - 芳基化的共价键。这种修饰激活了EGFR - Akt信号通路，从而抑制血清剥夺诱导的A549细胞凋亡。我们的研究揭示了一种通过共价结合激活EGFR的原始模式。我们提出了无配体情况下EGFR激活与癌症等环境污染物相关疾病之间的关联。
