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Curcumin blocks RON tyrosine kinase-mediated invasion of breast carcinoma cells

Madhusudhanan Narasimhan1, Sudhakar Ammanamanchi

  • 1Department of Medicine, Division of Hematology and Medical Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.

Cancer Research
|July 3, 2008
PubMed

Insights

Curcumin blocks breast cancer cell invasion by inhibiting the RON receptor tyrosine kinase. This natural compound down-regulates RON expression via the NF-kappaB pathway, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Macrophage-stimulating protein (MSP) promotes invasion in breast cancer cells expressing the receptor tyrosine kinase RON.
  • Previous work identified regulatory elements for RON gene expression.

Purpose of the Study:

  • To investigate the efficacy of curcumin in blocking RON tyrosine kinase-mediated invasion of breast cancer cells.
  • To elucidate the molecular mechanisms underlying curcumin's effect on RON expression and invasion.

Main Methods:

  • Reverse transcription-PCR and Western blot analysis to assess RON mRNA and protein levels.
  • Chromatin immunoprecipitation and site-directed mutagenesis to confirm transcription factor binding to the RON promoter.
  • Treatment with NF-kappaB inhibitor (PDTC) and siRNA knockdown of p65 to evaluate pathway involvement.

Main Results:

  • Curcumin down-regulated RON expression at both message and protein levels in MDA-MB-231 and MDA-MB-468 cells.
  • Curcumin treatment blocked MSP-induced invasion of breast cancer cells.
  • NF-kappaB p65 subunit was confirmed to bind to the RON promoter, and curcumin's action involved affecting p65 expression and activity.
  • Inhibition of p65 (using PDTC or siRNA) blocked RON expression and MSP-mediated invasion.

Conclusions:

  • Curcumin inhibits breast cancer cell invasion by down-regulating RON expression through the NF-kappaB pathway.
  • This study demonstrates for the first time the regulation of human RON gene expression by NF-kappaB.
  • Curcumin shows potential as a therapeutic agent to block RON tyrosine kinase-mediated invasion in carcinoma cells.

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