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This dissertation, Proteomic and Biochemical Analyses of Metal Ion-induced Carcinogenesis, Apoptosis and Apoptotic Resistance in Cultured Rat Lung Epithelial Cells by Tao-yin, Lau, 劉道然, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Proteomic and Biochemical Analyses of Metal Ion-induced Carcinogenesis, Apoptosis and Apoptotic Resistance in Cultured Rat Lung Epithelial Cells Submitted by Tao Yin LAU for the degree of Doctor of Philosophy at The University of Hong Kong in October 2005 Toxic metal ions represent major environmental hazards to human health. In particular, arsenic (As) and cadmium (Cd) compounds are ubiquitously distributed in nature. Recent epidemiological studies and clinical observations have indicated that arsenic and cadmium have associated with an increased risk of human cancer. In this study, the transient and long-term effects of arsenic and cadmium were investigated on our in vitro rat lung epithelial cell (LEC) model. Many studies in several cell types have used lethal concentrations of arsenic in the range of 50-500 M. Since the exposure of humans to arsenic is normally at a much lower level in the workplace or in daily life, we therefore aimed at re-defining the role of arsenic-induced carcinogenesis as well as apoptosis in LECs. On the other hand, it was hypothesized that the development of resistance to cadmium may drive carcinogenesis. This is achieved by selection of resistant cells in which apoptotic response is significantly attenuated. The induction of cadmium-resistance in LECs was used to explore the mechanisms of Cd-induced adaptation and carcinogenesis. Our results indicated that mitogen-activated protein kinase (MAPK) pathways might differentially contribute to cell growth and death in response to different dosages of arsenite. A low level (2 M) of arsenite stimulated the extracellular signal-regulated kinase (ERK) pathway and enhanced cell proliferation, whereas a high level (40 M) of arsenite stimulated the c-Jun N-terminal kinase (JNK) pathway, induced stress proteins and caused oxidative stress-induced apoptosis. Low levels of arsenite exerted its long-term effect in the process of carcinogenesis, transformation of LECs occurred after chronic arsenic treatment for 12 weeks. Importantly, the transformation efficiency and proteome alterations were more pronounced when arsenic was initiated with benzo[a]pyrene (B[a]P) than cells either exposed to arsenic or B[a]P alone. This further substantiates the notion that arsenic acts as a tumor promoter in the process of co-carcinogenesis. In addition, our results also demonstrated that cells developed resistance to apoptosis during cadmium-adaptation, possibly due to perturbation of the JNK pathway and the enhanced induction rate of metal binding protein metallothionein. Interestingly, the results from proteomic analysis showed that two intermediate filament proteins, cytokeratin 8 (CK8) and cytokeratin 14 (CK14) were increased significantly and stably maintained only in the adapted cells, but not in cadmium-exposed parental cells. It has been documented that CK8/18 provided resistance to tumor necrosis factor (TNF)-induced apoptosis and CK8 is a new cytoplasmic substrate of JNK. Similarly, CK14 is able to associate with TNF receptor 1-associated death domain protein (TRADD), suggesting that up-regulation of CK8 and CK14 may be responsible for apoptotic resistance in Cd-adapted cells. This acquired self-resistance to apoptosis could account for cadmium-induced carcinogenesis as this promotes neoplastic cell survival

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