K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis

Oncotarget. 2015 Aug 28;6(25):21328-40. doi: 10.18632/oncotarget.4049.


Estrogens are considered as a major risk factor of endometrial cancer. In this study, we identified a mechanism of tumorigenesis in which K-Ras protein is stabilized via estrogen signaling through the ER-α36 receptor. PKCδ was shown to stabilize K-Ras specifically via estrogen signaling. Estrogens stabilize K-Ras via inhibition of polyubiquitylation-dependent proteasomal degradation. Estrogen-induced cellular transformation was abolished by either K-Ras or PKCδ knockdown. The role of PKCδ in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKCδ inhibitor. Finally, levels of PKCδ correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKCδ up-regulation provides a potential therapeutic approach for treatment of endometrial cancer.

Keywords: K-Ras; PKCδ; endometrial cancer; estrogen; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Cycloheximide / pharmacology
  • Endometrial Neoplasms / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Estrogens / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase C-delta / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Estrogen / metabolism
  • Signal Transduction
  • Ubiquitination
  • ras Proteins / metabolism*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Estrogens
  • Receptors, Estrogen
  • Cycloheximide
  • Prkcd protein, mouse
  • PRKCD protein, human
  • Protein Kinase C-delta
  • Proteasome Endopeptidase Complex
  • ras Proteins