Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA with a 5-year survival rate less than 3% to 5%. Gemcitabine remains as a standard care for PDAC patients. Although protein neddylation is abnormally activated in many human cancers, whether neddylation dysregulation is involved in PDAC and whether targeting neddylation would sensitize pancreatic cancer cells to gemcitabine remain elusive. Here we report that high expression of neddylation components, NEDD8 and NAE1, are associated with poor survival of PDAC patients. Blockage of neddylation by MLN4924, a small molecule inhibitor targeting this modification, significantly sensitizes pancreatic cancer cells to gemcitabine, as evidenced by reduced growth both in monolayer culture and soft agar, reduced clonogenic survival, decreased invasion capacity, increased apoptosis, G2/M arrest, and senescence. Importantly, combinational treatment of MLN4924-gemcitabine near completely suppressed in vivo growth of pancreatic cancer cells. Mechanistically, accumulation of NOXA, a pro-apoptotic protein and ERBIN, a RAS signal inhibitor, appears to play, at least in part, a causal role in MLN4924 chemo-sensitization. Our study demonstrates that neddylation modification is a valid target for PDAC, and provides the proof-of-concept evidence for future clinical trial of MLN4924-gemcitabine combination for the treatment of pancreatic cancer patients.

中文翻译：

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Neddylation 修饰的抑制使胰腺癌细胞对吉西他滨敏感。

胰腺导管腺癌 (PDAC) 是美国第四大癌症死亡原因，5 年生存率低于 3% 至 5%。吉西他滨仍然是 PDAC 患者的标准治疗方法。尽管蛋白质neddylation在许多人类癌症中异常激活，但neddylation失调是否参与PDAC以及靶向neddylation是否会使胰腺癌细胞对吉西他滨敏感仍然难以捉摸。在此，我们报告 neddylation 成分 NEDD8 和 NAE1 的高表达与 PDAC 患者的不良生存率相关。MLN4924（一种针对这种修饰的小分子抑制剂）阻断neddylation，显着使胰腺癌细胞对吉西他滨敏感，单层培养物和软琼脂中的生长减少、克隆形成存活率降低、侵袭能力降低、细胞凋亡增加、G2/M 期阻滞证明了这一点和衰老。重要的是，MLN4924-吉西他滨的联合治疗几乎完全抑制了胰腺癌细胞的体内生长。从机制上讲，NOXA（一种促凋亡蛋白）和 ERBIN（一种 RAS 信号抑制剂）的积累似乎在 MLN4924 化疗敏化中起至少部分因果作用。我们的研究表明neddylation修饰是PDAC的有效靶点，并为未来MLN4924-吉西他滨组合治疗胰腺癌患者的临床试验提供了概念验证证据。