Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Annexin A2 / genetics
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Annexin A2 / metabolism*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Blotting, Western
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Cell Cycle / drug effects
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Cell Cycle / physiology*
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Cell Line, Tumor
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Cisplatin / pharmacology
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Culture Media, Serum-Free / pharmacology
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Mutation
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Protein Phosphatase 2 / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Transplantation, Heterologous
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bcl-2-Associated X Protein / metabolism
Substances
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Annexin A2
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Antineoplastic Agents
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Culture Media, Serum-Free
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Mitochondrial Proteins
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bcl-2-Associated X Protein
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Green Fluorescent Proteins
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Glycogen Synthase Kinase 3
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Protein Phosphatase 2
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2
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Htra2 protein, mouse
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Cisplatin