Ameliorative effects of selenium on arsenic-induced cytotoxicity in PC12 cells via modulating autophagy/apoptosis. (April 2018)

• Record Type: Journal Article
• Authors: Rahman, Md. Mostafizur; Uson-Lopez, Rachael A.; Sikder, Md. Tajuddin; Tan, Gongxun; Hosokawa, Toshiyuki; Saito, Takeshi; Kurasaki, Masaaki
• Is Part Of: Chemosphere. Volume 196(2018)
• Page Start: 453
• Page End: 466
• Publication Date: 2018-04
• Subjects: Malondialdehyde -- Autophagy -- Apoptosis -- Cytotoxicity -- Glutathione -- mTOR/Akt-pathway; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2017.12.149
• Languages: English
• ISSNs: 0045-6535

Abstract

Abstract: 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. Graphical abstract: Image Highlights: As 3+ induced cell death via intrinsic apoptotic pathway in PC12 cells. Se 4+ reduced As 3+ -induced oxidative stress in PC12 cells upon co-exposure. Se 4+ suppressed As 3+ -induced inhibition of p-mTOR/p-Akt, and NF-кB in PC12 cells. As 3+ -induced upregulation of Bax, caspase 3, 9 is inhibited by Se 4+ in co-exposure. Se 4+ hindered the cellular uptake of As 3+ in PC12 cells. Abstract : Selenium is capable to modulate arsenic-induced intrinsic apoptosis pathway via enhancement of mTOR/Akt autophagy signaling pathway in PC12 cells.