Abstract 707: Distinct roles of Na,K-ATPase function and expression in medulloblastoma

Abstract

Abstract Medulloblastoma, which usually arises in the cerebellum, is the most common malignant brain cancer in children and is still associated with substantial mortality and survivors often suffer from serious life-long therapy-related side effects. In recent years several medulloblastoma subtypes with distinct developmental origins, genetic profiles, pathway signatures, and clinicopathological features have been identified. The current consensus divides medulloblastoma tumors into four subgroups, WNT, sonic hedgehog (Shh), Group 3 and Group 4 allowing for different targeted therapeutic approaches. Not specifically restricted to a defined subgroup, aberrant activation of the epidermal growth factor receptor family (EGFR/ErbB) has been reported in a large percentage of medulloblastoma and has been associated with poor outcome. The Shh pathway is an important signaling pathway involved in cerebellar development. Shh is secreted from the Purkinje cells, and acts as a mitogen for cerebellar granule precursor (CGP) cells. Mutations leading to hyperactive Shh signaling have been associated with improper migration and differentiation of CGP cells and medulloblastoma formation. Still, the molecular targets contributing to Shh-mediated proliferation in these cells are poorly understood. Na,K-ATPase is a membrane protein that maintains intracellular ion homeostasis, and is responsible for generating ion gradients across cell membranes. Consisting of a catalytic alpha subunit and a beta subunit, the enzyme not only pumps sodium ions out and potassium ions into the cell using ATP but also functions a signaling scaffold and a cell adhesion molecule. Changes in Na,K-ATPase function and expression have been reported in various cancers and may contribute to tumor development and progression. We now show that the Na,K-ATPase beta1-subunit is drastically reduced in medulloblastoma tumors of mice with aberrant activation of Shh signaling. In addition, Shh activation prevented the upregulation of the beta1-subunit in primary cultures of normal cerebellar granule cells and the polycomb transcription factor Bmi1 that is induced upon activation of Shh signaling repressed beta1-subunit levels. Furthermore, shRNA-mediated knockdown of the beta1-subunit increased cell proliferation and tumorigenicity of medulloblastoma cells. Nevertheless, cardiac glycosides that inhibit the pump function of Na,K-ATPase inhibited EGF-induced signaling and cell motility suggesting that Na,K-ATPase alpha and beta subunit may have dual functions in CGP cells and medulloblastoma. Citation Format: Zhiqin Li, Alisa Litan, Seung Joon Lee, Bruce Graves, Sonali P. Barwe, Sigrid A. Langhans. Distinct roles of Na,K-ATPase function and expression in medulloblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 707. doi:10.1158/1538-7445.AM2015-707