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Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: role of

Jason R Hickok1, Sumit Sahni1, Yuliya Mikhed1

  • 1Departments of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60612.

The Journal of Biological Chemistry
|October 7, 2011
PubMed

Insights

Nitric oxide ((•)NO) up-regulates N-Myc downstream-regulated gene 1 (NDRG1) expression in breast cancer cells. This regulation depends on the chelatable iron pool and suppresses tumor cell migration.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Cancer research

Background:

  • N-Myc downstream-regulated gene 1 (NDRG1) is a stress-responsive protein implicated in cancer.
  • NDRG1 is known to be upregulated by iron chelators and hypoxia.
  • Regulation of NDRG1 by nitric oxide ((•)NO) has not been previously demonstrated.

Purpose of the Study:

  • To investigate the regulation of NDRG1 by nitric oxide ((•)NO) at the mRNA and protein levels.
  • To elucidate the role of the chelatable iron pool (CIP) and dinitrosyliron complexes (DNIC) in (•)NO-mediated NDRG1 expression.
  • To examine the functional consequences of (•)NO-induced NDRG1 expression on tumor cell behavior.

Main Methods:

  • Utilized HCC 1806 triple-negative breast cancer cells.
  • Administered physiological concentrations of (•)NO.
  • Manipulated the chelatable iron pool (CIP) to assess its role in (•)NO signaling.
  • Assessed NDRG1 mRNA and protein levels.
  • Evaluated tumor cell migration.
  • Investigated potential upstream regulators including HIF-1α, sGC, N-Myc, and c-Myc.

Main Results:

  • (•)NO up-regulates NDRG1 expression in a dose- and time-dependent manner in breast cancer cells.
  • NDRG1 upregulation by (•)NO suppresses tumor cell migration.
  • The chelatable iron pool (CIP) is essential for (•)NO-mediated NDRG1 expression and its phenotypic effects.
  • HIF-1α, sGC, N-Myc, and c-Myc were excluded as direct upstream mediators of this pathway.

Conclusions:

  • Nitric oxide ((•)NO) directly regulates NDRG1 expression in triple-negative breast cancer cells.
  • Chelatable iron availability is a critical determinant of (•)NO-induced NDRG1 signaling.
  • (•)NO-mediated NDRG1 induction inhibits tumor cell migration, suggesting a potential tumor-suppressive role in this context.

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