Lithium suppresses cell proliferation in prostate cancer

Lithium suppresses cell proliferation in prostate cancer

Sun A, Shanmugam I, Song J, Terranova PF, Thrasher JB, Li B. Lithium
suppresses cell proliferation by interrupting E2F-DNA interaction and
subsequently reducing S-phase gene expression in prostate cancer.
Prostate. 2007 Apr 17; [Epub ahead of print]
PMID: 17440966 [PubMed - as supplied by publisher]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?tmpl=NoSidebarfile&db=PubMed&cmd=Retrieve&list_uids=17440966&dopt=Abstract>

"BACKGROUND: Lithium is an existing drug for bipolar disorder
and its uptake was recently linked to reduced tumor incidence
compared to the general population. The major target of lithium
action is glycogen synthase kinase 3 (GSK-3). Since GSK-3
expression and activation are associated with prostate cancer
progression, the anti-cancer potential of lithium on prostate
cancer was investigated in this study. METHODS: Multiple
prostate cancer cell lines were treated with lithium chloride
(LiCl). Cell proliferation and cell cycle distribution were
analysed. DNA replication was determined using BrdU labeling
assay. Genome-wide screening of gene expression was performed
using cDNA microarray assay. GSK-3beta gene-specific silencing
was conducted using small interferencing RNA (siRNA)
transfection. E2 factor (E2F) transactivation was evaluated
using reporter gene assay and E2F-DNA interaction was
determined with chromatin-immunoprecipitation assay (ChIP).
RESULTS: LiCl significantly inhibited cell proliferation, which
was associated with reduced DNA replication and S-phase cell
cycle arrest. LiCl significantly decreased the expression of
multiple DNA replication-related genes, including cell division
cycle 6 (cdc6), cyclin A, cyclin E, and cdc25C, which are
regulated by E2F factor during cell cycle. A novel GSK-3-
specific inhibitor TDZD-8 and GSK-3beta siRNA also suppressed
the expression of these E2F target genes, indicating that LiCl-
induced anti-cancer effect was associated with GSK-3beta
inhibition. Furthermore, LiCl suppressed E2F transactivation by
interrupting the interaction of E2F1 factor with its target
gene promoter. CONCLUSIONS: These data indicated that LiCl
suppresses cancer cell proliferation by disrupting E2F-DNA
interaction and subsequent E2F-mediated gene expression in
prostate cancer. Prostate (c) 2007 Wiley-Liss, Inc."


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Matti Narkia