1] Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China [2] Laboratory of Food Engineering and Nutrition Research, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Science, Qingdao, China.
Cell Death Dis. 2013 Oct 3;4(10):e822. doi: 10.1038/cddis.2013.349.
Patulin (PAT) is one of the most common mycotoxins found in moldy fruits. Skin contact is one of the most likely exposure routes of PAT. Investigation of dermal toxicity of PAT is clearly needed and has been highlighted by WHO. In the present study, using human keratinocyte HaCaT cells as a model, we found that treatment with PAT caused an increased autophagosome accumulation. Measurements of autophagic flux demonstrated that the accumulation of autophagosomes by PAT was not directly due to enhanced autophagosome formation but due to inhibition of autophagosome degradation. Reductions in the activities of the lysosomal enzymes cathepsin B and cathepsin D by PAT might contribute to this inhibitory effect. Consistent with this, inhibition of autophagosome degradation by PAT resulted in accumulation of p62 that functioned as a pro-survival signal. The pro-survival function of p62 was found to be attributed to reactive oxygen species-mediated cytoprotective endoplasmic reticulum (ER) stress response. ER stress exerted cytoprotective effect via extracellular signal-regulated kinase1/2-dependent B-cell CLL/lymphoma 2-associated agonist of cell death inhibitory phosphorylation. Given the critical role of autophagy and its substrate p62 in carcinogenesis, our findings may have important implications in PAT-induced skin carcinogenesis.
棒曲霉素（PAT）是霉变水果中最常见的霉菌毒素之一。皮肤接触是 PAT 最有可能的暴露途径之一。世界卫生组织明确指出，需要对 PAT 的皮肤毒性进行调查。在本研究中，我们用人角质形成细胞 HaCaT 细胞作为模型，发现 PAT 处理会导致自噬体积累增加。自噬流的测量表明，PAT 诱导的自噬体积累不是直接由于自噬体形成增强，而是由于自噬体降解的抑制。PAT 降低溶酶体酶组织蛋白酶 B 和组织蛋白酶 D 的活性可能有助于这种抑制作用。与此一致，PAT 抑制自噬体降解导致 p62 的积累，p62 作为一种促生存信号发挥作用。发现 p62 的促生存功能归因于活性氧介导的保护性内质网（ER）应激反应。ER 应激通过细胞外信号调节激酶 1/2 依赖性 B 细胞 CLL/淋巴瘤 2 相关细胞死亡抑制磷酸化的激动剂发挥细胞保护作用。鉴于自噬及其底物 p62 在致癌作用中的关键作用，我们的研究结果可能对 PAT 诱导的皮肤致癌作用具有重要意义。
