Scatter factor protects tumor cells against apoptosis caused by TRAIL

Saijun Fan, Qinghui Meng, John J Laterra, Eliot M. Rosen

Research output: Contribution to journalArticle

Abstract

Scatter factor (SF) and its receptor c-Met are overexpressed in various tumor types, and their expression often correlates with a poor prognosis. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is a proposed tumor-specific chemotherapy agent, but its clinical usage is limited by acquisition of TRAIL resistance by tumors. The goals of this study were to determine whether and how SF protects tumor cells against TRAIL and whether SF-induced TRAIL resistance could be reversed. We used MTT assays, trypan blue dye exclusion assays, apoptosis assays, RNA interference, luciferase reporter assays, immunoprecipitation/western blotting, and other cell biological techniques to study SF protection of cultured human tumor cells against TRAIL. SF conferred resistance to TRAIL in various human prostate carcinoma and breast carcinoma cell lines. SF inhibited TRAIL-induced caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and cell death. SF protection against TRAIL required c-Akt; but unlike protection against adriamycin, it did not require Src signaling or the classical pathway of nuclear factor-kappaB activation. Protection against TRAIL was blocked by knockdown of X-linked inhibitor of apoptosis or FLICE-inhibitor protein (FLIP) (a component of the death-inducing signaling complex). We found that c-Met physically associates with several TRAIL receptors and SF regulates their protein stability. Protection against TRAIL was blocked by a novel small molecule inhibitor of c-Met (PHA665752) and by an inhibitor of cyclooxygenase 2. In conclusion, these findings elucidate potential mechanisms of TRAIL resistance in tumors that overexpress the SF/c-Met and identify possible means of reversing this resistance.

Original languageEnglish (US)
Pages (from-to)10-24
Number of pages15
JournalAnti-Cancer Drugs
Volume21
Issue number1
DOIs
StatePublished - Jan 2010

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Hepatocyte Growth Factor
Apoptosis
Neoplasms
Death Domain Receptor Signaling Adaptor Proteins
Proto-Oncogene Proteins c-met
TNF-Related Apoptosis-Inducing Ligand Receptors
Cultured Tumor Cells
Trypan Blue
Poly(ADP-ribose) Polymerases
Caspase 8
Protein Stability
Cyclooxygenase 2 Inhibitors
RNA Interference
Luciferases
Immunoprecipitation
Caspase 3
Doxorubicin
Prostate
Cell Death
Coloring Agents

Keywords

  • Apoptosis
  • C-Met
  • Death receptors
  • DR4
  • DR5
  • Hepatocyte growth factor
  • PHA665752
  • Scatter factor
  • TRAIL

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research
  • Oncology

Cite this

Scatter factor protects tumor cells against apoptosis caused by TRAIL. / Fan, Saijun; Meng, Qinghui; Laterra, John J; Rosen, Eliot M.

In: Anti-Cancer Drugs, Vol. 21, No. 1, 01.2010, p. 10-24.

Research output: Contribution to journalArticle

Fan, Saijun ; Meng, Qinghui ; Laterra, John J ; Rosen, Eliot M. / Scatter factor protects tumor cells against apoptosis caused by TRAIL. In: Anti-Cancer Drugs. 2010 ; Vol. 21, No. 1. pp. 10-24.
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