Unbalanced activation of ERK1/2 and MEK1/2 in apigenin-induced HeLa cell death

Exp Cell Res. 2004 Sep 10;299(1):15-26. doi: 10.1016/j.yexcr.2004.05.006.


Apigenin, a dietary bioflavonoid with anticarcinogenic properties, was highly cytotoxic for HeLa cells (incubated with 0.5% FBS). This effect was accompanied with a marked increase in ERK1/2 but not MEK1/2 phosphorylation. The cytotoxic effects of apigenin were attenuated by the stimulation of these cells with 10% FBS, which provoked an increase in the phosphorylation levels of MEK1/2 and ERK1/2. The steps in the ERK1/2 pathway relevant to the cytotoxic effects of apigenin, as well as the contribution of other signaling pathways, were investigated. The activation of the pathway by transfection with the constitutively active Ras mutant (RasV12) conferred protection to serum-starved HeLa cells against apigenin, whereas the constitutively active MEK(E) mutant did not. MEK inhibitors (PD098059 or U0126) blocked ERK1/2 phosphorylation induced by apigenin and conferred partial protection against this flavonoid. The effects of apigenin did not involve p38-MAPK or JNK1/2, and were not simply due to inhibition of PI3kinase or protein kinase CK2. These data suggest that the deregulation of the ERK1/2 pathway, due to the potentiation of ERK1/2 phosphorylation without increasing MEK1/2 phosphorylation, is involved in apigenin-induced HeLa cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apigenin
  • Blood Proteins / deficiency
  • Casein Kinase II
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Cytotoxins / toxicity
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / toxicity*
  • HeLa Cells
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinase Kinases / drug effects
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation / genetics
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Transfection
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Antineoplastic Agents
  • Blood Proteins
  • Cytotoxins
  • Enzyme Inhibitors
  • Flavonoids
  • Apigenin
  • Phosphatidylinositol 3-Kinases
  • Casein Kinase II
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins