The Role of Annexin A2 on Lung Cancer Cell Growthand Stress Response

• Main Authors: Chi-YunWang, 王琪芸
• Other Authors: Chiou-Feng Lin
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/35200615674619536298

博士 === 國立成功大學 === 基礎醫學研究所 === 100 === ANXA2, a calcium-dependent phospholipid binding protein, is widely expressed in cytoplasm and on the cell surface membrane while complexed with S100/A10. ANXA2 is involved in multiple cellular processes, including cell survival, growth, division, and differentiation. A lack of ANXA2 makes cells more sensitive to apoptotic stimuli. ANXA2 is overexpressed in many kinds of cancer and promotes tumorigenesis; however, the role of ANXA2 in lung cancer tumorigenesis has not been determined. This thesis is aimed at understanding the expression level of ANXA2 and the role of ANXA2 in lung tumorigenesis and further the regulatory mechanism of ANXA2 under stress. In the first part of this thesis, the expression of ANXA2 in patients with non-small cell lung cancer (NSCLC) was detected. Results show that ANXA2 is richly expressed in non-small cell lung cancer (NSCLC) and is positively correlated with poor prognosis. The survival time of patients with lower-ANXA2-expressed lung cancer is longer than whom with higher-ANXA2-expressed lung cancer. Moreover, ANXA2 is persistently expressed around the proliferative but not the necrotic region in BALB/c nude mice with human lung epithelial carcinoma A549 cell-derived tumor. In the second part of this thesis, the regulatory role of ANXA2 on cell cycle progression and cell proliferation was clarified. ANXA2 plays an important role in cancer cell proliferation, whereas the molecular mechanisms underlying the ANXA2-regulated cell cycle are still unknown. Results show that NSCLC A549 cells lacking ANXA2 exhibits defects in tumor growth in vivo and cell proliferation in vitro without cytotoxicity. ANXA2 knockdown induces cell cycle arrest at the G2 phase of interphase. Unexpectedly, ANXA2 silencing increases the expression of p53 and its downstream genes followed by a partial p53-mediated G2 arrest. Aberrant c-Jun N-terminal kinase (JNK) inactivation, which is observed in ANXA2 deficient cells, causes cell proliferation inhibition following G2 arrest. A lack of ANXA2 causes a loss of JNK-regulated c-Jun expression followed by a p53 transcriptional increase. These results demonstrate a novel role of ANXA2 in NSCLC cell proliferation by facilitating the cell cycle through the maintenance of JNK/c-Jun-inhibited p53. Further, the regulation of ANXA2 expression is still unclear. In the final part of this thesis, the regulation of ANXA2 expression was clarified under apoptotic stimuli. Here, we demonstrate a potential mechanism for apoptotic stimuli-induced ANXA2 cleavage. Results show that, under apoptotic stimuli, ANXA2 is cleaved via a time-dependent manner. Mechanistic studies have shown that protein phosphatase 2A (PP2A)-activated GSK-3 is essential for this process. Therefore, inhibiting GSK-3 reverses serum withdrawal-induced cell cycle inhibition or cisplatin-induced apoptosis. Furthermore, inhibiting serine proteases blocks apoptotic stimuli-induced ANXA2 cleavage. Bax activation and Mcl-1 destabilization, which is regulated by PP2A and GSK-3, causes ANXA2 cleavage via an Omi/HtrA2-dependent pathway. These results demonstrate that GSK-3 and Omi/HtrA2 synergistically cause ANXA2 cleavage and then cell cycle inhibition or apoptosis. Taken together, ANXA2 is overexpressed in lung cancer and loss of ANXA2 mediates p53 suppression of G2/M progression by targeting JNK/c-Jun. Under stress, GSK-3 and Omi/HtrA2 synergistically cause ANXA2 downregulation following cell apoptosis.