Inhibition of activation of dsRNA-dependent protein kinase and tumour growth inhibition

Helen L. Eley, Pria S. McDonald, Steve T. Russell, Michael J. Tisdale

Research output: Contribution to journalArticle

Abstract

Inhibition of dsRNA-activated protein kinase (PKR), not only attenuates muscle atrophy in a murine model of cancer cachexia (MAC16), but it also inhibits tumour growth. In vitro the PKR inhibitor maximally inhibited growth of MAC16 tumour cells at a concentration of 200 nM, which was also maximally effective in attenuating phosphorylation of PKR and of eukaryotic initiation factor (eIF)2 on the a-subunit. There was no effect on the growth of the MAC13 tumour, which does not induce cachexia, even at concentrations up to 1,000 nM. There was constitutive phosphorylation of PKR and eIF2a in the MAC16, but not in the MAC13 tumour, while levels of total PKR and eIF2a were similar. There was constitutive upregulation of nuclear factor-?B (NF-?B) in the MAC16 tumour only, and this was attenuated by the PKR inhibitor, suggesting that it arose from activation of PKR. In MAC16 alone the PKR inhibitor also attenuated expression of the 20S proteasome. The PKR inhibitor potentiated the cytotoxicity of both 5-fluorouracil and gemcitabine to MAC16 cells in vitro. These results suggest that inhibitors of PKR may be useful therapeutic agents against tumours showing increased expression of PKR and constitutive activation of NF-?B, and may also prove useful in sensitising tumours to standard chemotherapeutic agents.
LanguageEnglish
Pages651-659
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume63
Issue number4
DOIs
Publication statusPublished - Mar 2009

Fingerprint

Protein Kinases
Tumors
Chemical activation
Growth
Neoplasms
Phosphorylation
Cachexia
gemcitabine
Eukaryotic Initiation Factor-2
eIF-2 Kinase
Proteasome Endopeptidase Complex
Cytotoxicity
Muscular Atrophy
Fluorouracil
Muscle
Cells
Up-Regulation

Keywords

  • 20S proteasome
  • dsRNA-dependent protein kinase
  • PKR
  • eukaryotic initiation factor 2 alpha
  • nuclear factor-kappa B
  • antitumour action

Cite this

Eley, Helen L. ; McDonald, Pria S. ; Russell, Steve T. ; Tisdale, Michael J. / Inhibition of activation of dsRNA-dependent protein kinase and tumour growth inhibition. In: Cancer Chemotherapy and Pharmacology. 2009 ; Vol. 63, No. 4. pp. 651-659.
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Inhibition of activation of dsRNA-dependent protein kinase and tumour growth inhibition. / Eley, Helen L.; McDonald, Pria S.; Russell, Steve T.; Tisdale, Michael J.

In: Cancer Chemotherapy and Pharmacology, Vol. 63, No. 4, 03.2009, p. 651-659.

Research output: Contribution to journalArticle

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