Rahman Md Mostafizur, Uson-Lopez Rachael A, Sikder Md Tajuddin, Tan Gongxun, Hosokawa Toshiyuki, Saito Takeshi, Kurasaki Masaaki
Graduate School of Environmental Science, Hokkaido University, Japan; Department of Environmental Sciences, Jahangirnagar University, Bangladesh.
Graduate School of Environmental Science, Hokkaido University, Japan.
Chemosphere. 2018 Apr;196:453-466. doi: 10.1016/j.chemosphere.2017.12.149. Epub 2017 Dec 28.
Arsenic is well known toxicant responsible for human diseases including cancers. On the other hand, selenium is an essential trace element with significant chemopreventive effects, anticancer potentials and antioxidant properties. Although previous studies have reported antagonism/synergism between arsenic and selenium in biological systems, the biomolecular mechanism/s is still inconclusive. Therefore, to elucidate the molecular phenomena in cellular level, we hypothesized that co-exposure of selenium with arsenic may have suppressive effects on arsenic-induced cytotoxicity. We found that selenium in co-exposure with arsenic increases cell viability, and suppresses oxidative stress induced by arsenic in PC12 cells. Consequently, DNA fragmentation due to arsenic exposure was also reduced by arsenic and selenium co-exposure. Furthermore, western blot analyses revealed that simultaneous exposure of both metals significantly inhibited autophagy which further suppressed apoptosis through positively regulation of key proteins; p-mTOR, p-Akt, p-Foxo1A, p62, and expression of ubiquitin, Bax, Bcl2, NFкB, and caspases 3 and 9, although those are negatively regulated by arsenic. In addition, reverse transcriptase PCR analysis confirmed the involvement of caspase cascade in cell death process induced by arsenic and subsequent inhibition by co-exposure of selenium with arsenic. The cellular accumulation study of arsenic in presence/absence of selenium via inductively coupled plasma mass spectrometry confirmed that selenium effectively retarded the uptake of arsenic in PC12 cells. Finally, these findings imply that selenium is capable to modulate arsenic-induced intrinsic apoptosis pathway via enhancement of mTOR/Akt autophagy signaling pathway through employing antioxidant potentials and through inhibiting the cellular accumulation of arsenic in PC12 cells.
砷是一种众所周知的有毒物质，可导致包括癌症在内的人类疾病。另一方面，硒是一种必需的微量元素，具有显著的化学预防作用、抗癌潜力和抗氧化特性。尽管先前的研究报道了生物系统中砷和硒之间的拮抗/协同作用，但其生物分子机制仍无定论。因此，为了阐明细胞水平上的分子现象，我们假设硒与砷共同暴露可能对砷诱导的细胞毒性具有抑制作用。我们发现，与砷共同暴露的硒可提高细胞活力，并抑制PC12细胞中由砷诱导的氧化应激。因此，砷和硒共同暴露也减少了因砷暴露导致的DNA片段化。此外，蛋白质免疫印迹分析表明，两种金属同时暴露显著抑制自噬，通过对关键蛋白p-mTOR、p-Akt、p-Foxo1A、p62以及泛素、Bax、Bcl2、NFкB和半胱天冬酶3和9的表达进行正向调节，进一步抑制了细胞凋亡，尽管这些蛋白受砷的负调控。此外，逆转录酶PCR分析证实了半胱天冬酶级联反应参与了砷诱导的细胞死亡过程以及随后硒与砷共同暴露对其的抑制作用。通过电感耦合等离子体质谱对有无硒存在时砷的细胞积累研究证实，硒有效地阻碍了PC12细胞对砷的摄取。最后，这些发现表明，硒能够通过发挥抗氧化潜力、增强mTOR/Akt自噬信号通路以及抑制PC12细胞中砷的细胞积累，来调节砷诱导的内源性凋亡途径。
