Doctoral Dissertations

Date of Award

6-1984

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biomedical Sciences

Major Professor

Ann C. Marchok

Committee Members

John S. Cook, Julian Preston, Kai-Lin Lee, Peter A. Lalley

Abstract

Normal primary cell cultures (NPC) of rat tracheal epithelial cells require exogenous pyruvate for growth in vitro, whereas carcinogen-altered tracheal cells do not. The aim of this dissertation was to identify metabolic differences between these two cell types which may be related to their dissimilar growth requirements for exogenous pyruvate. The loss of requirement for exogenous pyruvate by the carcinogen-altered cells was used to selectively grow the altered cells, and these selected primary cell cultures (SPG) include cells from early stages in the progression of neoplasia.

A study of the effects of exogenous pyruvate on the growth and differentiation of NPC indicated that normal cells have a stringent and concentration dependent growth requirement for pyruvate. In pyruvate deficient medium, the degree of cell exfoliation and terminal differentiation (keratinization) gradually increased in NPC.

Distinct metabolic differences were found between NPC and SPC in the utilization of several key metabolites. Compared to SPC, the NPC have higher levels of hexose uptake, glycolysis, glucose flux in the pentose cycle, and exogenous pyruvate metabolism. Glutamine and alanine utilization are comparable in NPC and SPC, and similar levels of glutaminolysis are also present in both cell types. However, mitochondrial containing particulate fractions from SPC and two types of tumor-derived cell cultures have significantly higher levels of malic enzyme activity than particulate fractions of NPC.

The results of this study suggest that SPC do not achieve a growth advantage by: 1) increased rates of glycolysis; 2) a more efficient utilization of glucose; 3) major shifts in the utilization of glucose, alanine, or glutamine; and 4) increased levels of glutaminolysis.

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