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 key factor in cancer therapy. In this paper, we show that pretreatment of Burkitt's lymphoma cell lines expressing the c-met protooncogene with hepatocyte growth factor (HGF) protects them from death induced by DNA damaging agents 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 requiring pre-incubation with 100 ng/ml HGF for 48 h. Western blotting analysis and flow cytometric studies revealed that HGF inhibited doxorubicin- and 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 the development of a chemoresistant phenotype.
Skibinski
G
G
Department of Clinical and Surgical Sciences, University of Edinburgh, Royal Infirmary, Edinburgh EH3 9YW, UK. g.skibinski@qub.ac.uk
Skibinska
A
A
James
K
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D005047:Etoposide / Q000627:therapeutic use; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D005047:Etoposide; D004317:Doxorubicin; D019859:Proto-Oncogene Proteins c-met