Mistletoe lectin induces apoptosis and telomerase inhibition in human A253 cancer cells through dephosphorylation of Akt

Arch Pharm Res. 2004 Jan;27(1):68-76. doi: 10.1007/BF02980049.

Abstract

Mistletoe lectin has been reported to induce apoptosis in different cancer cell lines in vitro and to show antitumor activity against a variety of tumors in animal models. We previously demonstrated the Korean mistletoe lectin (Viscum album var. coloratum, VCA)-induced apoptosis by down-regulation of Bcl-2 and telomerase activity and by up-regulation of Bax through p53- and p21-independent pathway in hepatoma cells. In the present study, we observed the induction of apoptotic cell death through activation of caspase-3 and the inhibition of telomerase activity through transcriptional down-regulation of hTERT in the VCA-treated A253 cells. We also observed the inhibition of telomerase activity and induction of apoptosis resulted from dephosphorylation of Akt in the survival signaling pathways. In addition, combining VCA with the inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) upstream of Akt, wortmannin and LY294002 showed an additive inhibitory effect of telomerase activity. In contrast, the inhibitor of protein phosphatase 2A (PP2A), okadaic acid inhibited VCA-induced dephosphorylation of Akt and inhibition of telomerase activity. Taken together, VCA induces apoptotic cell death through Akt signaling pathway in correlated with the inhibition of telomerase activity and the activation of caspase-3. From these results, together with our previous studies, we suggest that VCA triggers molecular changes that resulting in the inhibition of cell growth and the induction of apoptotic cell death of cancer cells, which suggest that VCA may be useful as chemotherapeutic agent for cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Caspase 3
  • Caspases / adverse effects
  • Caspases / metabolism
  • Cell Line, Tumor*
  • Cell Survival / drug effects
  • Chromones / pharmacology
  • Drug Screening Assays, Antitumor / methods
  • Drug Synergism
  • Humans
  • Korea
  • Lectins / adverse effects*
  • Lectins / antagonists & inhibitors
  • Lectins / chemistry*
  • Lectins / isolation & purification
  • Mistletoe / chemistry*
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / pharmacology
  • Phosphorylation / drug effects
  • Plant Extracts / chemistry
  • Plant Preparations / adverse effects
  • Plant Preparations / antagonists & inhibitors
  • Plant Preparations / chemistry
  • Plant Proteins / adverse effects
  • Plant Proteins / antagonists & inhibitors
  • Plant Proteins / chemistry
  • Ribosome Inactivating Proteins, Type 2
  • Telomerase / antagonists & inhibitors*
  • Telomerase / genetics
  • Toxins, Biological / adverse effects
  • Toxins, Biological / chemistry
  • Up-Regulation

Substances

  • Chromones
  • Lectins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Plant Extracts
  • Plant Preparations
  • Plant Proteins
  • Ribosome Inactivating Proteins, Type 2
  • Toxins, Biological
  • ribosome inactivating protein, Viscum
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Telomerase
  • Phosphoric Monoester Hydrolases
  • CASP3 protein, human
  • Caspase 3
  • Caspases