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 classi fied small cell lung cancer, are characterized by the expression of ne uroendocrine (NE) features including AADC (aromatic amino acid decarbo xylase, previously called DOPA decarboxylase) and the production of ma ny peptide hormones. The general mechanisms by which most aspects of t he NE phenotype affect the clinical behavior of lung tumor cells are u nknown, but it is well recognized that peptide hormones can have syste mic effects (paraneoplastic syndromes) and several have been shown to be autocrine growth factors for cancer cells. In order to determine th e relationship between expression of different aspects of the NE pheno type in lung cancer cell lines, we have compared expression of a gene required for biosynthesis of some active peptide hormones (PAM, peptid ylglycine a-amidating monooxygenase) to the gene for AADC in 32 lung c ancer cell lines. Expression of these genes was quantified by both ste ady 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 wh ich had previously been shown to express NE markers, and several small cell lung cancer (SCLC) cell lines with previous low levels of AADC w ere included. PAM enzyme activity and Northern blot analysis showed a two to three log variation in levels of expression in both the small c ell and non-small cell lines. A smaller range was found for AADC expre ssion. Using the highly sensitive PAM enzyme assays, all cell lines we re found to express detectable PAM. PAM activities were secreted into the growth medium of all cell lines.There was no simple correlation ap parent between AADC and PAM gene expression in the lung cancer cell li nes. However, classic small cell lines demonstrated high levels of exp ression of both PAM and AADC genes, as did the carcinoid subset of the NSCLC lines. NSCLC lines expressed levels of PAM mRNA and enzyme acti vities equivalent to those of SCLC, but had infrequent expression of A ADC (principally only carcinoid NSCLC expressed AADC). These data demo nstrate that separate aspects of the NE phenotype can be differentiall y expressed in lung cancer histological sub-types. Expression of PAM e nzymes in all sub-types of lung cancer suggests that peptide prohormon e activation may be a common mechanism for autocrine growth stimulatio n even in non-NE NSCLC cell lines, or may reflect maintenance in cell lines of a common pathway of lung tumor promotion. (C) 1996 Wiley-Liss , Inc.