β8 Integrin Mediates Pancreatic Cancer Cell Radiochemoresistance
β8 Integrin Mediates Pancreatic Cancer Cell Radiochemoresistance
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DOI：
10.1158/1541-7786.mcr-18-1352
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发表时间：
2019-10-01
影响因子：
5.2
通讯作者：
Cordes, Nils
中科院分区：
文献类型：
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作者：
Jin, Sha;Lee, Wei-Chun;Cordes, Nils
胰腺导管腺癌（PDAC）间质由细胞外基质（ECM）蛋白组成，增加了治疗抗性和低生存率。众所周知，整合素介导的细胞/ECM相互作用控制癌细胞存活、增殖和治疗抗性。在这里，我们确定了β 8整合素在三维（3D），ECM为基础的细胞培养物中的高通量敲低筛选新的粘着斑蛋白的目标作为PDAC细胞放射化学抗性的关键决定因素。有趣的是，β 8整合素定位于高尔基体核周的PDAC细胞和切除标本PDAC患者。在放射性遗传毒性损伤后，β 8整联蛋白显示出微管依赖性核周至细胞质的转变，以及其蛋白质组相互作用组在细胞功能转运、催化和结合方面的强烈变化。该相互作用组的部分将β 8整联蛋白与自噬联系起来，自噬在β 8整联蛋白不存在的情况下减少。总的来说，我们的数据显示β 8整合素可以关键地共同调节PDAC细胞的放化抗性、胞内囊泡运输和照射后的自噬。
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.