High Dosage Lithium Treatment Induces DNA Damage and p57Kip2 Decrease

International Journal of Molecular Sciences

Emanuela Stampone¹  Clementina Barone¹  Fulvio Della Ragione¹  Arianna Aulitto¹  Adriana Borriello¹  Federica Verace¹  Debora Bencivenga¹ 

[1] Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy;

关键词: p57^kip2;    licl;    sh-sy5y;    oxidative stress;    dna damage;    dna damage response;   

DOI  :  10.3390/ijms21031169

来源: DOAJ

【 摘 要 】

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. p57^Kip2, 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 p57^Kip2 levels. Unexpectedly, we found that lithium downregulates the level of p57^Kip2 in a dose-dependent manner, mainly acting at the transcriptional level. A number of different approaches, mostly based on p57^Kip2 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 p57^Kip2 might be involved in DNA double-strand break responses. In conclusion, our study identified novel roles for p57^Kip2 in the molecular mechanism of lithium at high concentration and, more in general, in the process of DNA repair.

【 授权许可】

Unknown