A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma

• Published in: Nature communications Vol. 6; no. 1; p. 6289
• Main Authors: Kondapalli, Kalyan C, Llongueras, Jose P, Capilla-González, Vivian, Prasad, Hari, Hack, Anniesha, Smith, Christopher, Guerrero-Cázares, Hugo, Quiñones-Hinojosa, Alfredo, Rao, Rajini
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.02.2015
• Subjects: Animals; Brain cancer; Brain Neoplasms - metabolism; Cell division; Cell Line, Tumor; Cell Membrane - metabolism; Cell Movement; Cell Proliferation; Chemotherapy; Endosomes - metabolism; Epidermal growth factor; ErbB Receptors - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes; Genomes; Glioblastoma - metabolism; Humans; Hydrogen-Ion Concentration; Kinases; Lysosomes - metabolism; Male; Medical prognosis; Medicine; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neoplastic Stem Cells - cytology; Patients; Prognosis; Protons; Receptors, Transferrin - metabolism; Signal Transduction; Sodium-Hydrogen Exchangers - metabolism; Stem cells; Stem Cells - cytology; United States > US; Maryland; Baltimore Maryland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7289

Epidermal growth factor receptor (EGFR) signalling is a potent driver of glioblastoma, a malignant and lethal form of brain cancer. Disappointingly, inhibitors targeting receptor tyrosine kinase activity are not clinically effective and EGFR persists on the plasma membrane to maintain tumour growth and invasiveness. Here we show that endolysosomal pH is critical for receptor sorting and turnover. By functioning as a leak pathway for protons, the Na(+)/H(+) exchanger NHE9 limits luminal acidification to circumvent EGFR turnover and prolong downstream signalling pathways that drive tumour growth and migration. In glioblastoma, NHE9 expression is associated with stem/progenitor characteristics, radiochemoresistance, poor prognosis and invasive growth in vitro and in vivo. Silencing or inhibition of NHE9 in brain tumour-initiating cells attenuates tumoursphere formation and improves efficacy of EGFR inhibitor. Thus, NHE9 mediates inside-out control of oncogenic signalling and is a highly druggable target for pan-specific receptor clearance in cancer therapy.