LEUKEMIA INHIBITORY FACTOR INDUCES APOPTOSIS AND PROLIFERATION OF HUMAN CARCINOMA-CELLS THROUGH DIFFERENT ONCOGENE PATHWAYS

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells , and we thus analyzed its underlying mechanisms. Carcinoma cells cons titutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFR beta and gp130, respectively . Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF-7, ZR-75-1, Hs-700T and Panc-1) and suppressed cell grow th in 3 lines (AZ-521, GBK-1 and HT-29). LIF significantly induced an immediate early response of genes c-fos and junB 3 hr after stimulatio n, but not of c-jun during the process of proliferation of MCF-7 and H s-700T cells, with maximum levels at 30-60 min. The cell-cycle-related gene cyclin E was also induced in MCF-7 and Hs-700T cells, whereas cy clinA, cdk2, c-myc, c-myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ -521 and GBK-1 cells. LIF increased the number of TUNEL-positive cells in AZ-521 cells and DNA fragmentation in AZ-521 and GBK-1 cells. LIF induced apoptosis related genes c-myc and ICE during suppression of ce ll growth, but p53, P21, c-fos, cyclin A and cyclin E were not induced . Our results suggest that LIF is linked to cell proliferation and apo ptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of onco genes. (C) 1997 Wiley-Liss, Inc.