1. ¹Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA
2. ²Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA
3. ³Department of Psychiatry, New York University School of Medicine, New York, NY, USA
4. ⁴Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA

Correspondence: Professor PB Fisher, Departments of Urology and Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA. E-mail: pbf1@columbia.edu

Received 21 March 2007; Revised 25 June 2007; Accepted 28 June 2007; Published online 20 August 2007.

Abstract

Astrocyte elevated gene-1 (AEG-1) displays oncogenic properties. Its expression is elevated in diverse neoplastic states and it cooperates with Ha-ras to promote cellular transformation. Overexpression of AEG-1 augments invasion and anchorage-independent growth of transformed cells, while AEG-1 siRNA inhibits Ha-ras-mediated colony formation, supporting a potential functional role in tumorigenesis. Additionally, oncogenic Ha-ras induces AEG-1 expression through the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In the present study, we investigated whether AEG-1 could induce serum-independent cell growth, another property of oncogenes. Overexpression of AEG-1 inhibited serum starvation-induced apoptosis through activation of PI3K-Akt signaling, one of the effector pathways induced by activated Ras. AEG-1 also affected the phosphorylation state of Akt substrates that are implicated in apoptosis suppression, including glycogen synthase kinase 3, c-Myc, murine double minute 2, p53, p21/mda-6 and Bad. Additionally, AEG-1 blocked the activity of serum starvation-induced caspases. Taken together, these observations provide evidence that AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras and may perform a central role in Ha-ras-mediated carcinogenesis. Activation of survival pathways may be one mechanism by which AEG-1 exerts its oncogenic properties.