Abstract
Lithium salt is the first-line therapeutic option for bipolar disorder and has been proposed as a potential antitumoral drug. The effects of LiCl treatment were investigated in SH-SY5Y, a human neuroblastoma cell line and an in vitro model of dopaminergic neuronal differentiation. LiCl, at the dosage used in psychiatric treatment, does not affect cell proliferation, while at higher doses it delays the SH-SY5Y cell division cycle and for prolonged usage reduces cell viability. Moreover, the ion treatment affects DNA integrity as demonstrated by accumulation of p53 and γH2AX (the phosphorylated form of H2AX histone), two important markers of genome damage. p57Kip2, a CIP/Kip protein, is required for proper neuronal maturation and represents a main factor of response to stress including genotoxicity. We evaluated the effect of lithium on p57Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57Kip2 content handling, confirmed that the CKI/Kip reduction plays a key role in the DNA damage activated by lithium and suggests the unanticipated view that p57Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair.
Highlights
Since the last century, the therapeutic importance of lithium has been investigated, and many benefits of its use have been reported [1,2]
DNA damage response [25,26,27,28,29], and Li activity has been related to DNA damage [12], we investigated the effect of Li on p57 levels/activity in neuroblastoma cells in connection with cell phenotype
The effects of LiCl on cell proliferation and cell cycle distribution were investigated in the SH-SY5Y neuroblastoma cell line
Summary
The therapeutic importance of lithium has been investigated, and many benefits of its use have been reported [1,2]. The main medical use of Li treatment is mental illness. Li salt represents a well-established therapeutic option for bipolar disorder; it is employed in schizophrenia, major depression, and in several psychiatric diseases when other treatments fail [3]. Numerous toxic side effects were observed, only partially solved by the adjustment of the employed doses [2]. Safe therapeutic lithium blood levels range from 0.6 to 1.2 mM, while lithium toxicity can be observed when the serum concentration reaches 1.5 mM or higher [2]. Molecular mechanisms underlying Li action are complex and not completely clarified. This might be mostly due to the pleiotropy of Li molecular effects. None of the proposed biochemical mechanisms is sufficient to explain alone Li functions
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