Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition.

Abstract

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.

• Authors: Míriam Tarrado-Castellarnau, Roldán Cortés, Miriam Zanuy, Josep Tarragó-Celada, Ibrahim H Polat, Richard Hill, Teresa W M Fan, Wolfgang Link, Marta Cascante
• Journal: Pharmacological research (Pharmacol Res) Vol. 102 Pg. 218-34 (Dec 2015) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 26375988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Organoselenium Compounds
• Reactive Oxygen Species
• methylselenic acid
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Cisplatin

Topics

• 3T3 Cells
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Cycle (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Mice
• Organoselenium Compounds (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Reactive Oxygen Species (metabolism)