Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

J Lipid Res. 2013 Nov;54(11):3116-29. doi: 10.1194/jlr.M042283. Epub 2013 Aug 12.

Abstract

The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Among different structurally related COX-2 inhibitors, only celecoxib was found to cause apoptosis and cell death of human lung cancer cells (IC₅₀ values of 19.96 µM [A549], 12.48 µM [H460], and 41.39 µM [H358]) that was paralleled by a time- and concentration-dependent upregulation of COX-2 and peroxisome proliferator-activated receptor γ (PPARγ) at mRNA and protein levels. Apoptotic death of celecoxib-treated cancer cells was suppressed by the PPARγ antagonist GW9662 and by siRNA targeting PPARγ and, surprisingly, also by the selective COX-2 inhibitor NS-398 and siRNA targeting COX-2. NS-398 (1 µM) was shown to suppress celecoxib-induced COX-2 activity. Among the COX-2-dependent prostaglandins (PG) induced upon celecoxib treatment, PGD₂ and 15-deoxy-Δ¹²,¹⁴-PGJ₂ were found to induce a cytosol-to-nucleus translocation of PPARγ as well as a PPARγ-dependent apoptosis. Celecoxib-elicited PPARγ translocation was inhibited by NS-398. Finally, a COX-2- and PPARγ-dependent cytotoxic action of celecoxib was proven for primary human lung tumor cells. Together, our data demonstrate a proapoptotic mechanism of celecoxib involving initial upregulation of COX-2 and PPARγ and a subsequent nuclear translocation of PPARγ by COX-2-dependent PGs.

Keywords: cyclooxygenase-2; nonsteroidal antiinflammatory drugs; peroxisome proliferator activated receptor gamma; prostaglandins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Celecoxib
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Enzyme Induction / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Lung Neoplasms / pathology*
  • Nitrobenzenes / pharmacology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Prostaglandins / biosynthesis
  • Prostaglandins / pharmacology
  • Protein Transport / drug effects
  • Pyrazoles / pharmacology*
  • Sulfonamides / pharmacology*

Substances

  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Antineoplastic Agents
  • Cyclooxygenase 2 Inhibitors
  • Nitrobenzenes
  • PPAR gamma
  • Prostaglandins
  • Pyrazoles
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • Celecoxib