Abstract B51: Ligand-independent EphA2 signaling through Akt is preferentially activated in prostate cancer bone metastases and is important for tumor growth

Abstract

Abstract Prostate cancer progression to castration-resistance (CRPC) and metastasis represent the major challenges to effective prostate cancer therapy. PI3 kinase/Akt pathway activation has been linked to CRPC progression and metastasis, but the precise mechanisms have only been partially determined. Recently, we discovered that ligand-independent activation of the EphA2 receptor tyrosine kinase by Akt on a serine 897 site (S897) promotes cell migration and invasion, while stimulation with its ligand, ephrin-A1, downregulates EphA2 and inhibits migration and invasion. In the current study, we sought to determine whether ligand-independent EphA2 activation by Akt is linked to prostate cancer metastasis and progression to CRPC through biochemical and immunohistochemical analyses. Analysis of a panel of human prostate cancer tissues revealed EphA2 overexpression and increased S897 phosphorylation primarily in bone metastases, the primary metastatic site. Similarly, EphA2 was overexpressed in human cell lines from bone and brain metastases, but not in those from lymph node metastasis or primary tumor. Further analysis in a PTEN-deletion mouse model of aggressive prostate cancer revealed increased S897 phosphorylation in prostate glands from PTEN-null mice, compared to wild type prostate glands. To determine the potential link of EphA2 phosphorylation to CRPC progression, we compared S897 phosphorylation in xenograft tumors from both LAPC9 androgen-dependent and castration-resistant prostate cancer cell lines and found increased S897 phosphorylation in tumors from castration-resistant cells. Finally, abolishing S897 phosphorylation through the S897A point mutation inhibited growth of PC3 prostate cancer cells in a xenograft mouse model. Our study supports a link between ligand-independent EphA2 activation and prostate cancer progression and metastasis to bone, as well as primary tumor growth, highlighting a potential new mechanism involved in malignant prostate cancer progression. Citation Format: Aaron Petty, Hui Miao, Hong Guo, Colm Morrissey, Arul Chinnaiyan, Hong Wu, Bingcheng Wang. Ligand-independent EphA2 signaling through Akt is preferentially activated in prostate cancer bone metastases and is important for tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B51.