期刊
MOLECULAR CANCER RESEARCH
卷 17, 期 10, 页码 2126-2138出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-18-1352
关键词
-
资金
- European Union's Horizon 2020 research and innovation program under the Marie Skoodowska-Curie grant [642623]
Pancreatic ductal adenocarcinoma (PDAC) stroma, composed of extracellular matrix (ECM) proteins, promotes therapy resistance and poor survival rate. Integrin-mediated cell/ECM interactions are well known to control cancer cell survival, proliferation, and therapy resistance. Here, we identified beta 8 integrin in a high-throughput knockdown screen in three-dimensional (3D), ECM-based cell cultures for novel focal adhesion protein targets as a critical determinant of PDAC cell radiochemoresistance. Intriguingly, beta 8 integrin localizes with the golgi apparatus perinuclearly in PDAC cells and resection specimen from PDAC patients. Upon radiogenic genotoxic injury, beta 8 integrin shows a microtubule-dependent perinuclear-to-cytoplasmic shift as well as strong changes in its proteomic interactome regarding the cell functions transport, catalysis, and binding. Parts of this interactome link beta 8 integrin to autophagy, which is diminished in the absence of beta 8 integrin. Collectively, our data reveal beta 8 integrin to critically coregulate PDAC cell radiochemoresistance, intracellular vesicle trafficking, and autophagy upon irradiation.
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