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

  • Lu Y
  • Yamagishi N
  • Yagi T
 et al. 
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Abstract

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.

Author-supplied keywords

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

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Authors

  • Yanjun Lu

  • Nobuyuki Yamagishi

  • Takashi Yagi

  • Hiraku Takebe

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