The Skp2-SCF E3 Ligase Regulates Akt Ubiquitination, Glycolysis, Herceptin Sensitivity, and Tumorigenesis
Menée sur divers modèles murins de cancer du sein, cette étude met en évidence un mécanisme par lequel la ligase Skp2, en régulant l'activation de la kinase Akt, favorise le processus métastatique d'un cancer du sein HER2+
Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment. º Distinct E3 ligases regulate Akt ubiquitination, activation, and cancer development º Skp2 regulates Akt-mediated cancer glycolysis and tumorigenesis º Skp2 serves as a marker for poor prognosis in Her2-positive patients º Targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment Activation of aerobic glycolysis and tumor growth by EGF requires ubiquitination of Akt by the E3 ligase Skp2. Inhibiting Skp2 synergizes with herceptin to increase its effectiveness in mouse models of breast cancer.