Ganapathy Suthakar, Li Ping, Fagman Johan, Yu Tianqi, Lafontant Jean, Zhang Guojun, Chen Changyan
Center for Drug Development, Northeastern University, Boston, USA.
The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China; The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg, Sweden.
Toxicol Appl Pharmacol. 2016 Sep 1;306:98-104. doi: 10.1016/j.taap.2016.07.009. Epub 2016 Jul 15.
In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis. Thus, the results suggest that low doses of arsenic exposure, through attenuating p53-regulated tumor suppressive function, change the state of intracellular redox and create a microenvironment for tumorigenesis. Our study also provides the information for designing more effective strategies to prevent or treat human cancers initiated by arsenic exposure.
在饮用水以及工作场所或生活环境中，低剂量的砷能够存在并作为一种强效致癌物发挥作用。由于对环境中砷暴露的普遍性认识不足且相关信息匮乏，迫切需要阐明砷对人类健康致癌作用的潜在分子机制。在本研究中，我们证明低剂量的砷暴露会减轻或掩盖p53功能，并进一步扰乱细胞内氧化还原状态，从而引发持续性内质网（ER）应激并激活未折叠蛋白反应（UPR），进而导致细胞转化或肿瘤发生。因此，研究结果表明，低剂量的砷暴露通过减弱p53调节的肿瘤抑制功能，改变细胞内氧化还原状态，为肿瘤发生创造了微环境。我们的研究还为设计更有效的策略来预防或治疗由砷暴露引发的人类癌症提供了信息。
