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Effects of metformin on the PI3K/AKT/FOXO1 pathway in anaplastic thyroid Cancer cell lines

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Abstract

Background

The PI3K/AKT/FOXO signaling pathway plays an important role in the survival, proliferation and apoptosis of tumor cells. The aim of the present study was to explore whether metformin could affect insulin-promoting cell growth by regulation of this pathway.

Material and methods

Anaplastic thyroid cancer cells were treated with 0–60 mM metformin for 24, 48 and 72 h. Cell viability, morphology, apoptosis and migration were investigated by MTT assay, microscopy observation, AnexinV-PI and the wound healing assay, respectively. Expression levels of PI3K, AKT and FOXO1 were detected by RT-qPCR, and proteins phosphorylated levels were determined by ELISA.

Results

Metformin decreased cell viability and migration in a significant time-and dose-dependent manner, and induced apoptosis and morphological changes in the cells. RT-qPCR results showed that expression levels of PI3K, AKT and FOXO1 was inhibited by metformin (P < 0.05). However, there was no significant change in the expression level of AKT following metformin treatment for C643 cell line (P > 0.05). ELISA results showed that metformin treatment had no significant effects on the phosphorylated levels of PI3K, AKT and FOXO1 (P > 0.05).

Conclusuion

The downregulation of FOXO1 was intensified by metformin, but no increase in cell viability was observed following FOXO1 downregulation by metformin. However, the exact molecular mechanism of metformin on inhibition of the PI3K/AKT pathway and subsequent decrease in cell viability remains unclear and further studies are required for its clarification.

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Acknowledgements

The authors are grateful to Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences Tehran, Iran for their excellent technical and financial supports. This manuscript was extracted from PhD thesis of Zahra Nozhat (grant No: 852). The authors wish to acknowledge Ms. Niloofar Shiva for editing of English grammar and syntax of the manuscript.

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Authors and Affiliations

  1. Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Nozhat & Samira Mohammadi-Yeganeh

  2. Cellular and Molecular Endocrine Research Center, Research Institute of Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Nozhat, Maryam Zarkesh & Mehdi Hedayati

  3. Endocrine Research Center, Research Institute for Endocrine Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Feridoun Azizi

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  1. Zahra Nozhat
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  2. Samira Mohammadi-Yeganeh
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  3. Feridoun Azizi
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  4. Maryam Zarkesh
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  5. Mehdi Hedayati
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Correspondence to Mehdi Hedayati.

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Key Points

• Metformin decreased cell viability of ATC-derived cells in a dose-and time-dependent manner

• Decrease of cell viability by metformin significantly was associated with the downregulation of PI3K and AKT mRNA levels of the PI3K/AKT signaling pathway

• Metformin increased the downregulation of FOXO1but an increase in cell viability following FOXO1 downregulation was not observed

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Nozhat, Z., Mohammadi-Yeganeh, S., Azizi, F. et al. Effects of metformin on the PI3K/AKT/FOXO1 pathway in anaplastic thyroid Cancer cell lines. DARU J Pharm Sci 26, 93–103 (2018). https://doi.org/10.1007/s40199-018-0208-2

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  • DOI: https://doi.org/10.1007/s40199-018-0208-2

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