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Vol. 20, Issue 19, 4153-4161, October 1, 2009

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Glycogen Synthase Kinase-3 and Omi/HtrA2 Induce Annexin A2 Cleavage followed by Cell Cycle Inhibition and Apoptosis

Chi-Yun Wang^*,, Yee-Shin Lin^*,, Wu-Chou Su^*,, Chia-Ling Chen, and Chiou-Feng Lin^*,,

*Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; and Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

Submitted March 2, 2009; Revised June 26, 2009; Accepted July 27, 2009
Monitoring Editor: Jonathan Chernoff

Annexin A2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of annexin A2 makes cells more sensitive to apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced annexin A2 cleavage, which contributes to cell cycle inhibition and apoptosis. Annexin A2 was persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma cell A549-derived tumors. Knockdown expression of annexin A2 made cells susceptible to either serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Under apoptotic stimuli, annexin A2 was time-dependently cleaved. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated glycogen synthase kinase (GSK)-3 is essential for this process. Therefore, inhibiting GSK-3 reversed serum withdrawal-induced cell cycle inhibition and cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocked apoptotic stimuli-induced annexin A2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, caused annexin A2 cleavage via an Omi/HtrA2-dependent pathway. Taking these results together, we conclude that GSK-3 and Omi/HtrA2 synergistically cause annexin A2 cleavage and then cell cycle inhibition or apoptosis.

Address correspondence to: Chiou-Feng Lin (cflin{at}mail.ncku.edu.tw).

Abbreviations used: GSK, glycogen synthase kinase; PP, protein phosphatase; siRNA, small interfering RNA.