Hepatocyte growth factor (HGF) protects c-met-expressing Burkitt's lymphoma cell lines from apoptotic death induced by DNA damaging agents

The relative sensitivity of neoplastic cells to DNA damaging agents is a ke y factor in cancer therapy. In this paper, we show that pretreatment of Bur kitt's lymphoma cell lines expressing the c-met protooncogene with hepatocy te growth factor (HGF) protects them from death induced by DNA damaging age nts commonly used in tumour therapy. This protection was observed in assays based on morphological assessment of apoptotic cells and DNA fragmentation assays. The protection was dose- and time-dependent - maximal protection r equiring pre-incubation with 100 ng/ml HGF for 48 h. Western blotting analy sis and flow cytometric studies revealed that HGF inhibited doxorubicin- an d etoposide-induced decreases in the levels of the anti-apoptotic proteins Bcl-X-L. and to a lesser extent Bcl-2, without inducing changes in the pro- apoptotic Bax protein. Overall, these studies suggest that the accumulation of HGF within the microenvironment of neoplastic cells may contribute to t he development of a chemoresistant phenotype. (C) 2001 Elsevier Science Ltd . All rights reserved.