Hanqian Liang

Date of Award

2-25-1999

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Ann Bode

Abstract

Malignant cancers typically become more aggressive with time. This process, termed tumor or malignant progression, is associated with phenotypic changes within the tumor, such as loss of dependence upon growth factors or hormones, development of drug resistance, tissue invasiveness and metastatic ability. The observation of differences in levels of glutathione (GSH) and related enzymes, resistance to activation of apoptosis, and induction of transcription factors suggest that (1) oncogenic progression from growth factor dependency to autonomy in the Nb2 lymphoma cell model is associated with adaptive changes in the redox state of the cell and that these changes potentiate or facilitate the tumor's progression by increasing its resistance to oxidative stress; (2) an annulment of the tumor's increased resistance to oxidative stress is related to the nuclear factor kappa B (NF$\kappa$B); and (3) these changes may correlate with metastatic potential of the tumor in vivo. The purpose of this study was to examine these relationships in cultured prolactin (PRL)-dependent and PRL-independent rat lymphoma cell lines. The results from this study indicate that PRL-independent, Nb2-SFJCD1 cells are highly resistant to $\rm H\sb2O\sb2$ treatment compared to PRL-dependent cell. The resistance to $\rm H\sb2O\sb2$-induced DNA fragmentation (an indication of apoptosis) was related to the capacity of the Nb2-SFJCD1 cells to markedly increase GSH and glutathione peroxidase activity following exposure to oxidative stress. Resistance to $\rm H\sb2O\sb2$-induced apoptosis induced by $\rm H\sb2O\sb2$ was also associated with increased NF$\kappa$B binding in Nb2-SFJCD1. The relationship between PRL-dependency, PRL-independency, and the ability to resist oxidative stress requires additional study; however, the current results indicate a potential relationship among glutathione level, resistance to apoptosis, NF$\kappa$B induction and the onset of cell autonomy.

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