Expression in human lung cancer cell lines of genes of prohormone processing and the neuroendocrine phenotype.
Lung tumor cells and cell lines, principally the histologically classified small cell lung cancer, are characterized by the expression of neuroendocrine (NE) features including AADC (aromatic amino acid decarboxylase, previously called DOPA decarboxylase) and the production of many peptide hormones. The general mechanisms by which most aspects of the NE phenotype affect the clinical behavior of lung tumor cells are unknown, but it is well recognized that peptide hormones can have systemic effects (paraneoplastic syndromes) and several have been shown to be autocrine growth factors for cancer cells. In order to determine the relationship between expression of different aspects of the NE phenotype in lung cancer cell lines, we have compared expression of a gene required for biosynthesis of some active peptide hormones (PAM, peptidylglycine alpha-amidating monooxygenase) to the gene for AADC in 32 lung cancer cell lines. Expression of these genes was quantified by both steady state Northern blot analysis and radiochemical enzymatic activity measurements. To ensure a range of expression of NE markers, non-small cell lung cancer (NSCLC) cell lines were chosen to include several which had previously been shown to express NE markers, and several small cell lung cancer (SCLC) cell lines with previous low levels of AADC were included. PAM enzyme activity and Northern blot analysis showed a two to three log variation in levels of expression in both the small cell and non-small cell lines. A smaller range was found for AADC expression. Using the highly sensitive PAM enzyme assays, all cell lines were found to express detectable PAM. PAM activities were secreted into the growth medium of all cell lines. There was no simple correlation apparent between AADC and PAM gene expression in the lung cancer cell lines. However, classic small cell lines demonstrated high levels of expression of both PAM and AADC genes, as did the carcinoid subset of the NSCLC lines. NSCLC lines expressed levels of PAM mRNA and enzyme activities equivalent to those of SCLC but had infrequent expression of AADC (principally only carcinoid NSCLC expressed AADC). These data demonstrate that separate aspects of the NE phenotype can be differentially expressed in lung cancer histological sub-types. Expression of PAM enzymes in all sub-types of lung cancer suggests that peptide prohormone activation may be a common mechanism for autocrine growth stimulation even in non-Ne NSCLC cell lines, or may reflect maintenance in cell lines of a common pathway of lung tumor promotion.
Vos
M D
MD
Biomarkers and Prevention Research Branch, National Cancer Institute, Rockville, Maryland 20850-3300, USA.
Scott
F M
FM
Iwai
N
N
Treston
A M
AM
D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D004296:Dopa Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009384:Paraneoplastic Endocrine Syndromes / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D004296:Dopa Decarboxylase