TRANSITION FROM SCLC TO NSCLC PHENOTYPE IS ACCOMPANIED BY AN INCREASED TRE-BINDING ACTIVITY AND RECRUITMENT OF SPECIFIC AP-1 PROTEINS

Transitions from small cell (SCLC) to non-small cell lung cancer (NSCL C) cells have been documented both in vitro and in vivo and are though t to be an important step during tumor progression of human small cell lung cancer towards a treatment-resistant tumor state. We have screen ed NSCLC and SCLC cell lines for differences in the composition of nuc lear transcription factors using consensus oligonucleotide sequences ( SRE, Ets, TRE, CRE, B-motif, GAS, E-box), We found NSCLC cells to exhi bit significantly higher AP-1 binding activity than SCLC cells consist ent with the increased expression of CD44, an AP-1 target gene. To gai n more insight into the molecular mechanisms underlying these differen ces, we analysed SCLC cell lines (NCI-N592 and NCI-H69) which were phe notypically transformed into NSCLC-type cells by transfection with act ivated H-l ns and c-myc oncogenes, In these cells, I as-induced transi tion is accompanied by a strong induction of AP-l-binding activity alo ng with increased expression of CD 44 mRNA and protein. When analysing the composition of the AP-1 complex in more detail and comparing ras- induced versus phorbol ester-induced changes, we found Fra-1 to be the major component induced in ras-transfected but not in phorbol-ester t reated or non-treated parental SCLC cells. This finding is paralleled by the observation that among the various members of the Fos and Jun f amily analysed (c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunD, JunB) fra-1 is the only gene to be exclusively expressed in NSCLC cells but not in c ells of SCLC origin. Our data, thus, point to a histiotype-related mec hanism of recruitment among AP-1 proteins which may have bearings on t he fate of lung cancer development.