Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents

Oncogene. 1998 Jul 16;17(2):131-41. doi: 10.1038/sj.onc.1201943.


Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-XL as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Breast Neoplasms / etiology
  • Carcinoma / etiology*
  • Cell Cycle
  • Cells, Cultured
  • DNA Damage*
  • Dogs
  • Doxorubicin / adverse effects
  • Epithelial Cells / drug effects*
  • Female
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Mammary Neoplasms, Animal / etiology
  • Mice
  • Mutagens / adverse effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-met / metabolism
  • Signal Transduction
  • X-Rays / adverse effects
  • bcl-X Protein


  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Mutagens
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Hepatocyte Growth Factor
  • Doxorubicin
  • Proto-Oncogene Proteins c-met