3-OH flavone inhibition of epidermal growth factor-induced proliferaton through blocking prostaglandin E2 production

Int J Cancer. 2004 Feb 10;108(4):502-10. doi: 10.1002/ijc.11581.


Epidermal growth factor (EGF) has been shown to induce proliferation in cells, however, the role of prostaglandin E(2) (PGE(2)) plays in EGF-induced proliferation in still unclear. EGF and PGE(2) showed proliferation responses in epidermoid carcinoma cell A431 by MTT and [(3)H] thymidine incorporation assay. Activation of the EGF receptor and extracellular signal-regulated protein kinases (ERK1/2), but not p38 and JNK, appeared 10 min after EGF treatment, whereas total amounts of ERK1/2, p38 and JNK remained unchanged in A431 cells, accompanied by induction of COX-2 and PGE(2) production. PD98059, a specific ERK1/2 inhibitor, inhibited EGF-induced proliferation with concomitant decreases in ERK1/2 phosphorylation and COX-2/PGE(2) induction. Non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and diclofenac, a COX activity inhibitor, inhibited EGF-induced proliferation by blocking PGE(2) production. The addition of PGE(2) reversed the inhibitory effects of PD98059, aspirin, and diclofenac on EGF-induced proliferation. This suggests that COX-2/PGE(2) activation involves in EGF-induced proliferation and locates at the downstream of ERK1/2 activation. Furthermore, the natural product, 3-OH flavone, showed the most-potent inhibitory activity on EGF-induced proliferation among 9 structurally-related compounds, and suppression of EGF receptor phosphorylation, ERK1/2 phosphorylation, and COX-2/PGE(2) production by 3-OH flavone was identified. PGE(2) addition attenuates the inhibitory activity of 3-OH flavone on EGF-induced proliferation by MTT assay and colony formation by soft agar assay. Additionally, 3-OH flavone also showed more-specific inhibition on EGF- than on fetal bovine serum (FBS)-induced proliferation in A431 cells. Results of our present study provide evidence to demonstrate that PGE(2) is an important downstream molecule in EGF-induced proliferation, and 3-OH flavone, which inhibits PGE(2) production by blocking MAPK cascade, might reserve potential for development as an anti-cancer drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Carcinoma, Squamous Cell / enzymology
  • Carcinoma, Squamous Cell / pathology*
  • Cell Division / drug effects
  • Colony-Forming Units Assay
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / metabolism*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / antagonists & inhibitors*
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Flavonoids / pharmacology*
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Tetrazolium Salts
  • Thiazoles
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Flavonoids
  • Isoenzymes
  • Membrane Proteins
  • Tetrazolium Salts
  • Thiazoles
  • Epidermal Growth Factor
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • ErbB Receptors
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • thiazolyl blue
  • Dinoprostone
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • 3-hydroxyflavone