Masters Theses

Date of Award

8-2002

Degree Type

Thesis

Degree Name

Master of Science

Major

Comparative and Experimental Medicine

Major Professor

Hildegard M. Schuller

Committee Members

Michael D. Karlstad, Sharon M. Patton, Potgieter L.N.D

Abstract

Human pulmonary adenocarcinoma (PAC), which originates from bronchiolar epitheliaVClara cells (P ACC) or the alveolar type II cells (PAC type II), constitutes one of the most rapidly rising lung cancer types. The occurrence of PAC in smoking and nonsmoking individuals suggests that other factors besides smoking contribute to the development and progression of PAC. Earlier studies showed the presence of beta-adrenergic/cAMP growth pathway in PACC. Consequently, beta-adrenergic stimulants in various drug formulations that are used in the management of chronic respiratory diseases have been proposed as potential risk factors for the development of PAC. On the other hand, little is known about the role of this pathway in the proliferation of PAC type II. Using thymidine incorporation, this study showed that the two PAC phenotypes have differential response to the betaadrenergic/cAMP stimulation. Isoproterenol (broad-spectrum beta-adrenergic agonist) and forskolin (adenylyl cyclase stimulator) induced significant proliferative response in NCI-H322 cell line (PACC). Both beta-1 and beta-2 adrenergic receptors and cAMP are involved in this proliferative response as shown by selective receptor and enzyme inhibitors. On the other hand, A549 cells (PAC-type II) were inhibited by forskolin while being unresponsive to beta-adrenergic stimulation. Accordingly, forskolin caused significant and persistent activation of the extracellular signal regulated kinase (ERK.1/2) in NCI-H322 cells in contrast to A549 cells, in which inhibition was observed. Cyclic AMP immunoassay of basal and stimulant-induced cAMP amount showed marked difference between the two cell lines. The basal cAMP content in A549 cells was significantly lower than that of NCI-H322 cells. Moreover, isoproterenol had no effect while forskolin had significant but moderate rise of cAMP. By contrast, both isoproterenol and forskolin induced a marked and significant accumulation of cAMP in NCI-H322 cells. In both cell lines, significantly higher proliferative response was observed in low serum than in high serum culture condition. The epidermal growth factor receptor (EGFR)­ mediated growth pathway is common to both cell lines as demonstrated by the use of AG 1478 (EGFR-specific tyrosine kinase inhibitor). Furthermore, AG 1478 inhibited isoproterenol but not forskolin-induced proliferation in NCI-H322 cells, implying the existence of cAMP dependent and independent growth pathways and transactivation of the EGFR. The present study demonstrated an important difference between two cancer cell phenotypes that are generally grouped as PAC. The implication of this distinction in relation to cancer chemoprevention approaches and chronic management of respiratory diseases with beta-adrenergic stimulants was emphasized. On the other hand, the EGFR growth pathway is commonly expressed and plays a central role in the proliferation of both PAC phenotypes. Consequently, the EGFR pathway may provide a common chemotherapeutic target in broad family of cancer types and phenotypes with diverse growth pathways.

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