Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin.
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This study received financial support from the Ministerio de Ciencia e Innovación, Spain (SAF2011-25726), the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR)-Generalitat de Catalunya (2014SGR1017), the Fundação para a Ciência e a Tecnologia (FCT) Research Center (grant UID/BIM/04773/2013 CBMR 1334) and the Tarrado-Castellarnau et al. National Institute of Health, USA (grant numbers 1R01CA118434-01A2 and 1P01CA163223-01A1). We would also like to acknowledge the National Science Foundation, USA (grant number EPS-0447479) for support of the 18.8 Tesla NMR system at the University of Louisville. RH is the recipient of a FCT 2012 research grant (SFRH/BPD/84634/2012) FCT. MC acknowledges the support received through the prize ICREA Academia for excellence in research, funded by ICREA Foundation-Generalitat de Catalunya.
Tarrado-Castellarnau, Míriam; Cortés, Roldán; Zanuy, Miriam; Tarragó-Celada, Josep; Polat, Ibrahim H.; Hill, Richard; Fan, Teresa W-M; Link, Wolfgang; and Cascante, Marta, "Methylseleninic Acid Promotes Antitumour Effects via Nuclear FOXO3a Translocation through Akt Inhibition" (2015). Toxicology and Cancer Biology Faculty Publications. 42.