Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development

Saketh S. Dinavahi, Yu Chi Chen, Raghavendra Gowda, Pavan Kumar Dhanyamraju, Kishore Punnath, Dhimant Desai, Arthur Berg, Scot R. Kimball, Shantu Amin, Jin Ming Yang, Gavin P. Robertson

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer.

Original languageEnglish
Article number3481
JournalInternational Journal of Molecular Sciences
Issue number7
StatePublished - Apr 1 2022

Bibliographical note

Funding Information:
Funding: G.P.R.: This research was funded by the Foreman Foundation for Melanoma Research; the Geltrude Foundation; the Penn State Chocolate Tour Cancer Research Fund; and the Pennsylvania Department of Health using Tobacco CURE Funds (SAP #4100072562). S.R.K.: NIH grant R01DK015658.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • Anti-cancer drug
  • Cholesterol
  • Drug development
  • EEF2K
  • LDLR
  • Melanoma
  • Nanotechnology
  • SREBP2

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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