Tumor-associated down-regulation of 15-lipoxygenase-1 is reversed by celecoxib in colorectal cancer

Ann Surg. 2005 Jun;241(6):941-6; discussion 946-7. doi: 10.1097/01.sla.0000164177.95620.c1.


Objective: To evaluate the role of celecoxib on 15-lipoxygenase-1 (15-LOX-1) expression, protein levels, and rates of apoptosis in colorectal cancer cell lines. Also, to evaluate the expression of 15-LOX-1 in human normal mucosa, adenoma, and carcinoma with correlation to overall survival.

Summary background data: The function of 15-LOX-1 is to maintain normal rates of apoptosis (programmed cell death). Decreased apoptosis is one mechanism of cancer growth and dissemination. It is our hypothesis that expression of 15-LOX-1 is reduced in human colorectal cancer (CRC) and the administration of celecoxib can reverse this process and induce apoptosis.

Methods: Effect of celecoxib in cell culture: The effect of 40 micromol/L celecoxib was compared with untreated controls in tissue culture utilizing HT-29 and DLD-1 CRC cell lines. Expression of 15-LOX-1 protein was measured by immunoblot. Induction of apoptosis was evaluated by annexin V staining. All data are presented as mean +/- SEM, with significance defined as P < 0.05. 15-LOX-1 in human CRC: From February 1998 to January 2002, 126 patients underwent surgical resection of either colorectal adenomas (n = 24) or carcinomas (n = 102), or both (n = 25). Tissue was macrodissected, snap frozen, and stored at -80 degrees C. After tissue processing, RNA was extracted and gene expression of 15-LOX-1 was quantified utilizing ABI prism real-time quantitative RT-PCR. Significance evaluated by the Wilcoxon signed rank test.

Results: Effect of celecoxib in cell culture: After 72 hours of treatment with celecoxib, immunoblot demonstrated a 1.5- to 2-fold increase in 15-LOX-1 protein expression in HT-29 and DLD-1 cells, respectively. Celecoxib produced greater than a 2-fold increase in the rate of apoptosis compared with control cells in both cell lines (P < 0.05). 15-LOX-1 in human CRC: The mean age of the patients was 62 +/- 1 years; 78% were white and 48% were female. The mean size of the polyps and cancers were 3.0 +/- 0.4 and 5.0 +/- 0.1 cm, respectively. Expression of 15-LOX-1 relative to S9 was 30 in normal mucosa and significantly down-regulated to 11 in adenomas and 16 in carcinomas (P < 0.05).

Conclusions: 15-LOX-1 gene expression is significantly reduced in both human colorectal adenomas and carcinomas and associated with decreased survival. Administration of celecoxib restores 15-LOX-1 protein expression and induces apoptosis. Down-regulation of 15-LOX-1 is an early event in the adenoma to carcinoma sequence, and reversal with celecoxib may represent one mechanism for chemoprevention of polyps or treatment of carcinomas.

MeSH terms

  • Adenoma / enzymology
  • Adenoma / genetics*
  • Adenoma / mortality
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Arachidonate 15-Lipoxygenase / genetics*
  • Arachidonate 15-Lipoxygenase / metabolism
  • Blotting, Western
  • Carcinoma / metabolism
  • Carcinoma / mortality
  • Celecoxib
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cyclooxygenase Inhibitors / therapeutic use
  • Down-Regulation / drug effects*
  • Eicosanoids / analysis
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immunohistochemistry
  • Linoleic Acids / metabolism
  • Male
  • Middle Aged
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Tumor Cells, Cultured


  • Cyclooxygenase Inhibitors
  • Eicosanoids
  • Linoleic Acids
  • Pyrazoles
  • Sulfonamides
  • 13-hydroxy-9,11-octadecadienoic acid
  • Arachidonate 15-Lipoxygenase
  • Celecoxib