Na+/H+ exchanger NHE9 affects tumor progression of human glioblastomas by altering endosomal pH (893.34)

Abstract

Na+(K+)/H+ Exchangers (NHEs) are a large family of transport proteins that conduct electroneutral countertransport of cations with protons across lipid bilayers. A newly discovered Na+/H+ Exchanger, NHE9 (SLC9A9), has recently been shown to localize to a perinuclear region corresponding to recycling endosomes, where it is thought to regulate luminal pH and control cargo trafficking and degradation. Given the mounting evidence implicating NHE9 in neurological diseases including autism and ADHD, we explored the functional consequence of altered NHE9 expression levels in brain cancer.Glioblastoma Multiforme (GBM) is the most aggressive form of malignant glioma that accounts for over 50% of all gliomas and is frequently characterized by the amplification and membrane persistence of epidermal growth factor receptor (EGFR). EGFR signaling is tightly regulated by receptor endocytosis and lysosomal‐mediated degradation, and we postulated that NHE9 might alter this pathway. Here, we have found that levels of NHE9 are amplified in a large subset of GBMs. Using primary GBM cell cultures with naturally high or low levels of NHE9, we have found that altering those levels regulates tumorigencity and migratory capacity in vitro and in nude mouse xenografts. Furthermore, increased NHE9 levels alkalinizes the luminal pH of endosomes, which inhibits EGFR degradation and promotes oncogenic signaling downstream of MAPK and Akt. Finally, we show that inhibiting NHE9 with amiloride‐derived inhibitor EIPA increases EGFR responsiveness to Erlotinib. Our findings demonstrate that NHE9 is a target gene that should be explored as a treatment for a subset of GBMs.Grant Funding Source: Supported by NIH grant R01 DK054214