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Published on: October 12, 2013

Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin E2 production in human

Ravinder Tammali1, Kota V Ramana, Sharad S Singhal

  • 1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0647, USA.

Cancer Research
|October 5, 2006
PubMed

Insights

Aldose reductase (AR) inhibition blocks prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in colon cancer cells, halting tumor growth. Targeting AR offers a new therapeutic strategy for colon cancer progression.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Nonsteroidal anti-inflammatory drugs targeting prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) inhibit colon cancer progression.
  • Aldose reductase (AR) metabolizes toxic aldehydes and their conjugates.
  • AR's role in colon cancer cell growth and prostaglandin synthesis is not fully understood.

Purpose of the Study:

  • To investigate the role of aldose reductase (AR) in mediating growth factor-induced prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) up-regulation in human colon cancer cells.
  • To evaluate the therapeutic potential of AR inhibition in colon cancer progression.

Main Methods:

  • Human colon cancer cells (Caco-2) were treated with AR inhibitors (sorbinil, antisense ablation) and growth factors.
  • COX-2 activity, protein, and mRNA levels were assessed.
  • Activation of nuclear factor-kappaB (NF-κB) and protein kinase C (PKC) was measured.
  • Cell cycle analysis was performed.
  • In vivo studies involved administration of AR-small interfering RNA (siRNA) to mice bearing human colon adenocarcinoma xenografts.

Main Results:

  • AR inhibition prevented fibroblast growth factor- and platelet-derived growth factor-induced up-regulation of PGE2 synthesis and COX-2 expression in Caco-2 cells.
  • AR inhibition decreased NF-κB and PKC activation and Caco-2 cell proliferation at the S phase.
  • Treatment with toxic lipid aldehydes (4-hydroxy-trans-2-nonenal [HNE] and its glutathione conjugate [GS-HNE]) increased COX-2 expression and PGE2 production.
  • AR inhibition blocked HNE- and GS-HNE-induced COX-2 and PGE2 up-regulation.
  • In vivo administration of AR-siRNA completely arrested tumor progression in mice.

Conclusions:

  • Aldose reductase (AR) is an essential mediator of growth factor-induced COX-2, PGE2, and colon cancer cell growth.
  • Inhibition of AR represents a novel therapeutic strategy for preventing colon cancer progression.

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