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β8 Integrin Mediates Pancreatic Cancer Cell Radiochemoresistance.

Abstract
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 β8 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, β8 integrin localizes with the golgi apparatus perinuclearly in PDAC cells and resection specimen from PDAC patients. Upon radiogenic genotoxic injury, β8 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 β8 integrin to autophagy, which is diminished in the absence of β8 integrin. Collectively, our data reveal β8 integrin to critically coregulate PDAC cell radiochemoresistance, intracellular vesicle trafficking, and autophagy upon irradiation. IMPLICATIONS: This study identified β8 integrin as an essential determinant of PDAC cell radiochemosensitivity and as a novel potential cancer target.
AuthorsSha Jin, Wei-Chun Lee, Daniela Aust, Christian Pilarsky, Nils Cordes
JournalMolecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 10 Pg. 2126-2138 (10 2019) ISSN: 1557-3125 [Electronic] United States
PMID31337672 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2019 American Association for Cancer Research.
Chemical References
  • Integrin beta Chains
  • integrin beta8
Topics
  • Carcinoma, Pancreatic Ductal (drug therapy, metabolism, pathology, radiotherapy)
  • Cell Line, Tumor
  • Chemoradiotherapy
  • Drug Resistance, Neoplasm
  • Humans
  • Integrin beta Chains (biosynthesis, genetics, metabolism)
  • Pancreatic Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
  • Radiation Tolerance
  • Signal Transduction
  • Survival Rate
  • Transfection

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