Abstract
Metformin has recently emerged as a key player in promotion of neuroblastoma differentiation and neurite outgrowth. However, molecular mechanisms of how metformin promotes cellular differentiation have not yet been fully elucidated. In this study, we investigated how metformin promotes cell differentiation, via an inhibition of cell proliferation, by culturing SH-SY5Y neuroblastoma cells with or without metformin. Pretreatment with reactive oxygen species (ROS) scavenger, NAC, revealed that ROS plays a crucial role in induction of cell differentiation. Cell differentiation was observed under various morphological criteria: extension of neuritic processes and neuronal differentiation markers. Treatment with metformin significantly increased neurite length, number of cells with neurite, and expression of neuronal differentiation markers, β-tubulin III and tyrosine hydroxylase (TH) compared with untreated control. Further investigation found that metformin significantly decreased Cdk5 but increased Sox6 during cell differentiation. Analysis of the mechanism underlying these changes using Cdk5 inhibitor, roscovitine, indicated that expressions of Cdk5 and Sox6 corresponded to metformin treatment. These results suggested that metformin produces neuronal differentiation via Cdk5 and Sox6. In addition, phosphorylated Erk1/2 was decreased while phosphorylated Akt was increased in metformin treatment. Taken together, these findings suggest that metformin promotes neuronal differentiation via ROS activation through Cdk5/Sox6 crosstalk, relating to Erk1/2 and Akt signaling.
Highlights
Cell differentiation is a process by which nonspecialized cells have become specialized mature cells
A relation between cell proliferation and cell differentiation is observed in G1 phase, regulated by Cdk-cyclin activity and the differentiation induced by transcription factors [5]
To investigate the effect of metformin on SHSY5Y cell proliferation, cells were cultured with various concentrations of metformin (0.5, 1, 5, 10, and 20 mM) for 24 h
Summary
Cell differentiation is a process by which nonspecialized cells have become specialized mature cells. Cell differentiation has been widely studied because it can be used as an alternative therapeutic treatment such as degeneration of neuronal cells [1]. SH-SY5Y neuroblastoma cell is considered as in vitro models of neuronal function and differentiation because SHSY5Y can differentiate into mature neuron-like phenotype characterized by neuronal markers [2, 3]. Cell differentiation plays a remarkable inverse association with cell proliferation [4]. A relation between cell proliferation and cell differentiation is observed in G1 phase, regulated by Cdk-cyclin activity and the differentiation induced by transcription factors [5].
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