Details

Autor(en) / Beteiligte

• Yu, Wan-Ni
• Nogueira, Veronique
• Sobhakumari, Arya
• Patra, Krushna C.
• Bhaskar, Prashanth T.
• Hay, Nissim

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2015-07, Vol.12 (4), p.610-621

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Systemic Akt1 deletion regresses p53−/− thymic lymphoma, emulating p53 restoration•Akt inhibition regresses tumors that are not driven by Akt activation•Skp2 inhibits apoptosis by inhibiting FasL and Fas expression•Overexpression of Skp2 could exert resistance to Akt inhibition Yu et al. have deleted Akt1 after tumor onset in p53−/− mice. 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.