Cap-dependent translation initiation factor, eIF4E, is the target for Ouabain-mediated inhibition of HIF-1α

Ji Cao, Lingjuan He, Guanyu Lin, Chunqi Hu, Rong Dong, Jun Zhang, Hong Zhu, Yongzhou Hu, Carston R Wagner, Qiaojun He, Bo Yang

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that mediates the adaptation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Recently, HIF-1α has been recognized as the critical target of cardiac glycosides for cancer therapy, but the molecular mechanism of cardiac glycosides' inhibition of HIF-1α is still poorly understood. In the present study, we observed that neither HIF-1α mRNA levels nor HIF-1α protein degradation are affected by Ouabain. However, Ouabain was found to be associated with the regulation of HIF-1α translation. Basing on in silico, in vitro and ex vivo models of translation processing, further studies revealed that eIF4E plays a critical role in the inhibitory effect of Ouabain on HIF-1α protein synthesis, rather than mTORC1, eIF2α signaling or Na+/K+-ATPase inhibition. Mechanistically, Ouabain directly binds eIF4E, disrupts eIF4E/eIF4G association (200 μM, Inhibit rate = 61 ± 3%) but not the eIF4E/mRNA complex formation (200 μM, Inhibit rate = 18 ± 5%) both in vitro and in cells, thereby inhibiting the intracellular cap-dependent translation. The association between Ouabain and eIF4E not only raises the hope of using cardiac glycosides for cancer therapeutics more rational, but also offers a pharmacologic means for developing novel anti-cancer HIF-1α antagonists.

Original languageEnglish (US)
Pages (from-to)20-30
Number of pages11
JournalBiochemical Pharmacology
Volume89
Issue number1
DOIs
StatePublished - May 1 2014

Fingerprint

Hypoxia-Inducible Factor 1
Peptide Initiation Factors
Ouabain
Cardiac Glycosides
Heart Neoplasms
Association reactions
Messenger RNA
Computer Simulation
Proteolysis
Adenosine Triphosphatases
Tumors
Neoplasms
Proteins
Transcription Factors
Therapeutics
Cells
Tissue
Degradation

Keywords

  • Cancer therapy
  • Hypoxia
  • Hypoxia inducible factor
  • Translation
  • eIF4E

Cite this

Cap-dependent translation initiation factor, eIF4E, is the target for Ouabain-mediated inhibition of HIF-1α. / Cao, Ji; He, Lingjuan; Lin, Guanyu; Hu, Chunqi; Dong, Rong; Zhang, Jun; Zhu, Hong; Hu, Yongzhou; Wagner, Carston R; He, Qiaojun; Yang, Bo.

In: Biochemical Pharmacology, Vol. 89, No. 1, 01.05.2014, p. 20-30.

Research output: Contribution to journalArticle

Cao, Ji ; He, Lingjuan ; Lin, Guanyu ; Hu, Chunqi ; Dong, Rong ; Zhang, Jun ; Zhu, Hong ; Hu, Yongzhou ; Wagner, Carston R ; He, Qiaojun ; Yang, Bo. / Cap-dependent translation initiation factor, eIF4E, is the target for Ouabain-mediated inhibition of HIF-1α. In: Biochemical Pharmacology. 2014 ; Vol. 89, No. 1. pp. 20-30.
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AU - Dong, Rong

AU - Zhang, Jun

AU - Zhu, Hong

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AU - Wagner, Carston R

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