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 inMLN4924 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.
[1]Univ Michigan, Div Radiat & Canc Biol, Dept Radiat Oncol, 4424B MS 1,1301 Catherine St, Ann Arbor, MI 48109 USA.
[2]Zhejiang Univ, Inst Translat Med, Sch Med, Hangzhou, Zhejiang, Peoples R China.
[3]Zhejiang Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou, Zhejiang, Peoples R China.
[4]Fudan Univ, Collaborat Innovat Ctr Canc Med, Shanghai Canc Ctr, Canc Inst,Dept Oncol,Shanghai Med Coll, Shanghai 200032, Peoples R China.
[5]Univ Michigan, Dept Biostat, 4424B MS 1,1301 Catherine St, Ann Arbor, MI 48109 USA.
[6]Shanghai Res Inst Tradit Chinese Med, Oncol Inst Tradit Chinese Med, Shanghai 200032, Peoples R China.
[7]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Dept Oncol, Shanghai 200032, Peoples R China.
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