Targeting β2 subunit of Na ⁺/K ⁺-ATPase induces glioblastoma cell apoptosis through elevation of intracellular Ca ²⁺

Abstract

Glioblastoma (GBM) is the most frequent brain cancer with poor prognosis and few therapies and urgently requires effective treatments. Na ⁺/K ⁺-ATPase is considered as a target for GBM therapy and development of anticancer drugs. Cardiac glycosides bind the Na ⁺/K ⁺-ATPase α subunit to inhibit enzymatic activity and are promising candidates for anticancer drug development including GBM. However, the comparatively higher doses required for effective anticancer actions cause severe cardiotoxicity. Selectively targeting the ATPase Na ⁺/K ⁺ transporting subunit beta 2 (ATP1B2) that is not expressed in the heart might avoid the cardiotoxicity. However, the effect of targeting ATP1B2 in GBM remains unknown. In this study, we found that high ATP1B2 expression is significantly associated with poor prognosis of patients with GBM. ATP1B2 silencing in GBM cells resulted in remarkably cell cycle arrest at the G2/M phase and apoptosis with concomitant increase in intracellular Ca ²⁺ and activation of p38 kinase, similar to Na ⁺/K ⁺-ATPase inhibition by the classic cardiac glycoside digoxin. ATP1B2 is expressed higher in glioblastoma stem-like cells (GSCs) than in GBM cells and its downregulation induces apoptosis of GSCs. Furthermore, inducible ATP1B2 knockdown significantly inhibit tumor growth in vivo. Our data suggest ATP1B2 has potential as a therapeutic target for GBM.