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First published on May 8, 2006; DOI: 10.1124/mol.106.024059

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Received for publication March 6, 2006.
Revised May 8, 2006.
Accepted for publication May 8, 2006.

Lithium Inhibits Ceramide- and Etoposide-induced PP2A Methylation, Bcl-2 Dephosphorylation, Caspase-2 Activation and Apoptosis

Chia-Ling Chen 1, Chiou-Feng Lin 1, Chi-Wu Chiang 1, Ming-Shiou Jan 2, Yee-Shin Lin 1*

1 National Cheng Kung University 2 Chung-Shan Medical University

* Address correspondence to: E-mail: yslin1{at}mail.ncku.edu.tw

Abstract

Lithium confers cell protection against stress and toxic stimuli. Although lithium inhibits a number of enzymes, the anti-apoptotic mechanisms of lithium remain unresolved. Here we report a novel role of lithium on the blockage of ceramide- and etoposide-induced apoptosis via inhibition of protein phosphatase 2A (PP2A) activity. Overexpression of PP2A resulted in caspase-2 activation, mitochondrial damage, and cell apoptosis that were inhibited by okadaic acid (OA) and lithium. Lithium and OA abrogated ceramide- and etoposide-induced Bcl-2 dephosphorylation at serine 70. Furthermore, ceramide- and etoposide-induced PP2A activation involved methylation of PP2A C subunit, which lithium suppressed. Lithium caused dissociation of PP2A B subunit from the PP2A core enzyme, whereas ceramide caused recruitment of the B subunit. Taken together, lithium exhibited an anti-apoptotic effect by inhibiting Bcl-2 dephosphorylation and caspase-2 activation, which involved, at least in part, a mechanism of downregulating PP2A methylation and PP2A activity.


Key words: Protein ser/thr Phosphatases, Apoptosis


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