Hepatocyte Growth Factor/Scatter Factor Blocks the Mitochondrial Pathway of Apoptosis Signaling in Breast Cancer Cells

Min Gao, Saijun Fan, Itzhak D. Goldberg, John Laterra, Richard N. Kitsis, Eliot M. Rosen

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The cytokine hepatocyte growth factor/scatter factor (HGF/SF) has been found to protect a variety of epithelial and cancer cell types against cytotoxicity and apoptosis induced by DNA damage, but the specific apoptotic signaling events and the levels at which they are blocked by HGF/SF have not been identified. We found that treatment of MDA-MB-453 human breast cancer cells with adriamycin (also known as doxorubicin, a DNA topoisomerase IIα inhibitor) induced a series of time-dependent events, including the mitochondrial release of cytochrome c and apoptosis-inducing factor, mitochondrial membrane depolarization, activation of a set of caspases (caspase-9, -3, -7, -2, and -8), cleavage of poly(ADP-ribose) polymerase (PARP), and up-regulation of expression of the Fas ligand. All of these events were blocked by preincubation of the cells with HGF/SF. In contrast, the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethylketone blocked some of these events (e.g. caspase-3 activation and PARP cleavage) but did not block cytochrome c release or mitochondrial depolarization. These findings suggest that HGF/SF functions, in part, upstream of the mitochondria to block mitochondrial apoptosis signaling, prevent activation of multiple caspases, and protect breast cancer cells against apoptosis.

Original languageEnglish (US)
Pages (from-to)47257-47265
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number50
DOIs
StatePublished - Dec 14 2001

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Hepatocyte Growth Factor
Cells
Apoptosis
Breast Neoplasms
Poly(ADP-ribose) Polymerases
Chemical activation
Depolarization
Caspases
Cytochromes c
Caspase 3
Doxorubicin
Apoptosis Inducing Factor
Topoisomerase II Inhibitors
Mitochondria
Fas Ligand Protein
Caspase Inhibitors
Caspase 9
Mitochondrial Membranes
Cytotoxicity
DNA Damage

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hepatocyte Growth Factor/Scatter Factor Blocks the Mitochondrial Pathway of Apoptosis Signaling in Breast Cancer Cells. / Gao, Min; Fan, Saijun; Goldberg, Itzhak D.; Laterra, John; Kitsis, Richard N.; Rosen, Eliot M.

In: Journal of Biological Chemistry, Vol. 276, No. 50, 14.12.2001, p. 47257-47265.

Research output: Contribution to journalArticle

Gao, Min ; Fan, Saijun ; Goldberg, Itzhak D. ; Laterra, John ; Kitsis, Richard N. ; Rosen, Eliot M. / Hepatocyte Growth Factor/Scatter Factor Blocks the Mitochondrial Pathway of Apoptosis Signaling in Breast Cancer Cells. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 50. pp. 47257-47265.
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