Systemic Akt1 Deletion after Tumor Onset in p53(-/-) Mice Increases Lifespan and Regresses Thymic Lymphoma Emulating p53 Restoration

Cell Rep. 2015 Jul 28;12(4):610-21. doi: 10.1016/j.celrep.2015.06.057. Epub 2015 Jul 16.

Abstract

Akt is frequently activated in human cancers. However, it is unknown whether systemic inhibition of a single Akt isoform could regress cancer progression in cancers that are not driven by Akt activation. We systemically deleted Akt1 after tumor onset in p53(-/-) mice, which develop tumors independently of Akt activation. Systemic Akt1 deletion regresses thymic lymphoma in p53(-/-) mice emulating p53 restoration. Furthermore, pharmacological inhibition of Akt selectively kills thymic lymphoma cells and not primary thymocytes. Mechanistically, Akt1 inhibition in p53(-/-) thymic lymphoma inhibits Skp2 expression and induces FasL, which is the primary cause of cell death. Skp2 exerts resistance to cell death by antagonizing the induction of FasL and reducing FAS expression, which is linked to cyclin D1 expression. The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Fas Ligand Protein / metabolism
  • Humans
  • Longevity*
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Mice
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • S-Phase Kinase-Associated Proteins / genetics
  • S-Phase Kinase-Associated Proteins / metabolism
  • Thymocytes / metabolism*
  • Thymocytes / pathology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Fas Ligand Protein
  • S-Phase Kinase-Associated Proteins
  • Tumor Suppressor Protein p53
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt