Academic Journal
A Novel NHE1-Centered Signaling Cassette Drives Epidermal Growth Factor Receptor–Dependent Pancreatic Tumor Metastasis and Is a Target for Combination Therapy
| العنوان: | A Novel NHE1-Centered Signaling Cassette Drives Epidermal Growth Factor Receptor–Dependent Pancreatic Tumor Metastasis and Is a Target for Combination Therapy |
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| المؤلفون: | Rosa Angela Cardone, Maria Raffaella Greco, Katrine Zeeberg, Angela Zaccagnino, Mara Saccomano, Antonia Bellizzi, Philipp Bruns, Marta Menga, Christian Pilarsky, Albrecht Schwab, Frauke Alves, Holger Kalthoff, Valeria Casavola, Stephan Joel Reshkin |
| المصدر: | Neoplasia: An International Journal for Oncology Research, Vol 17, Iss 2, Pp 155-166 (2015) |
| بيانات النشر: | Elsevier, 2015. |
| سنة النشر: | 2015 |
| المجموعة: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na+/H+ exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1476-5586 1522-8002 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S1476558614001936; https://doaj.org/toc/1476-5586; https://doaj.org/toc/1522-8002 |
| DOI: | 10.1016/j.neo.2014.12.003 |
| URL الوصول: | https://doaj.org/article/3cb735e04e994897beba64f72621b1dc |
| رقم الانضمام: | edsdoj.3cb735e04e994897beba64f72621b1dc |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14765586 15228002 |
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| DOI: | 10.1016/j.neo.2014.12.003 |