A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma
| Autor: | José P. Llongueras, Vivian Capilla-Gonzalez, Anniesha Hack, Hugo Guerrero-Cazares, Alfredo Quiñones-Hinojosa, Kalyan C. Kondapalli, Hari Prasad, Rajini Rao, Christopher Smith |
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| Přispěvatelé: | National Institutes of Health (US), American Heart Association, Johns Hopkins University, American Physiological Society |
| Rok vydání: | 2015 |
| Předmět: |
Male
General Physics and Astronomy Receptor tyrosine kinase Mice 0302 clinical medicine Cell Movement SLC9A9 Epidermal growth factor receptor Receptor sorting endosomes EGFR inhibitors NHE9 0303 health sciences Multidisciplinary Brain Neoplasms pH Hydrogen-Ion Concentration Middle Aged Prognosis 3. Good health Cell biology ErbB Receptors Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Neoplastic Stem Cells Female Protons Signal transduction Stem cell Signal Transduction Sodium-Hydrogen Exchangers Endosome EGFR Mice Nude Endosomes Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Na+/H+ exchanger stem cells trafficking Cell Line Tumor Receptors Transferrin Animals Humans Gene silencing Gene Silencing Cell Proliferation 030304 developmental biology Gene Expression Profiling Cell Membrane General Chemistry transferrin receptor biology.protein Glioblastoma Lysosomes Neoplasm Transplantation |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Nature communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms7289 |
| Popis: | 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. This work was supported by grants from the National Institutes of Health NS070024 (A.Q.H.), and DK054214 and GM62142 (R.R.). K.C.K. was supported by an American Heart Association postdoctoral fellowship (11POST7380034); J.P. received support from the Johns Hopkins PREP program; H.P. was a Fulbright Fellow supported by the International Fulbright Science and Technology Award; and A.H. was a Porter fellow of the American Physiological Society. |
| Databáze: | OpenAIRE |
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