Ubiquitin Proteasomal System (UPS) and autophagy dysregulation initiate cancer. These pathways are regulated by zinc finger proteins. Trivalent inorganic arsenic (iAs) displaces zinc from zinc finger proteins disrupting functions of important cellular proteins. The effect of chronic environmental iAs exposure (100 nM) on UPS has not been studied. We tested the hypothesis that environmental iAs exposure suppresses UPS, activating autophagy as a compensatory mechanism. We exposed skin (HaCaT and Ker-CT; independent quadruplicates) and lung (BEAS-2B; independent triplicates) cell cultures to 0 or 100 nM iAs for 7 or 8 weeks. We quantified ER stress (XBP1 splicing employing Reverse Transcriptase -Polymerase Chain Reaction), proteasomal degradation (immunoblots), and initiation and completion of autophagy (immunoblots). We demonstrate that chronic iAs exposure suppresses UPS, initiates autophagy, but suppresses autophagic protein degradation in skin and lung cell lines. Our data suggest that chronic iAs exposure inhibits autophagy which subsequently suppresses UPS.

中文翻译：

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慢性砷暴露抑制蛋白酶体和自噬蛋白降解

泛素蛋白酶体系统 (UPS) 和自噬失调会引发癌症。这些途径受锌指蛋白调节。三价无机砷 (iAs) 会取代锌指蛋白中的锌，从而破坏重要细胞蛋白的功能。尚未研究长期环境 iAs 暴露 (100 nM) 对 UPS 的影响。我们测试了这样的假设：环境 iAs 暴露会抑制 UPS，激活自噬作为补偿机制。我们将皮肤（HaCaT 和 Ker-CT；独立四份）和肺（BEAS-2B；独立三份）细胞培养物暴露于 0 或 100 nM iAs 7 或 8 周。我们量化了 ER 应激（采用逆转录酶聚合酶链反应的 XBP1 剪接）、蛋白酶体降解（免疫印迹）以及自噬的启动和完成（免疫印迹）。我们证明，长期接触 iAs 会抑制 UPS，启动自噬，但会抑制皮肤和肺细胞系中的自噬蛋白降解。我们的数据表明，长期接触 iAs 会抑制自噬，从而抑制 UPS。