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PMID: 19656851 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis.

Molecular biology of the cell ·Vol. 20 ·No. 19 ·2009-10-00 ·Pages 4153-61

Wang CY, Lin YS, Su WC, Chen CL, Lin CF

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.

MeSH Terms
Animals Annexin A2/genetics,metabolism Antineoplastic Agents/pharmacology Apoptosis/drug effects,physiology Blotting, Western Cell Cycle/drug effects,physiology Cell Line, Tumor Cisplatin/pharmacology Culture Media, Serum-Free/pharmacology Glycogen Synthase Kinase 3/genetics,metabolism Green Fluorescent Proteins/genetics,metabolism High-Temperature Requirement A Serine Peptidase 2 Humans Membrane Potential, Mitochondrial/drug effects Mice Mice, Inbred BALB C Mice, Nude Mitochondrial Proteins/genetics,metabolism Mutation Neoplasms, Experimental/genetics,metabolism,pathology Protein Phosphatase 2/metabolism RNA Interference Reverse Transcriptase Polymerase Chain Reaction Serine Endopeptidases/genetics,metabolism Transplantation, Heterologous bcl-2-Associated X Protein/metabolism
Chemicals
Annexin A2 Antineoplastic Agents Culture Media, Serum-Free Mitochondrial Proteins bcl-2-Associated X Protein Green Fluorescent Proteins Glycogen Synthase Kinase 3 Protein Phosphatase 2 Serine Endopeptidases HTRA2 protein, human High-Temperature Requirement A Serine Peptidase 2 Htra2 protein, mouse Cisplatin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang Chi-Yun
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Lin Yee-Shin
Su Wu-Chou
Chen Chia-Ling
Lin Chiou-Feng
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1939-4586
DOI
10.1091/mbc.e09-02-0174
Published
2009-10-00
Epub
2009-00-05
Pages
4153-61
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC2754929
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.e09-02-0174 PMC Full Text View journal details
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