title: Targeting the neddylation pathway to suppress the growth of prostate cancer cells: therapeutic implication for the men's cancer.
abstract: The neddylation pathway has been recognized as an attractive anticancer target in several malignancies, and its selective inhibitor, MLN4924, has recently advanced to clinical development. However, the anticancer effect of this compound against prostate cancer has not been well investigated. In this study, we demonstrated that the neddylation pathway was functional and targetable in prostate cancer cells. Specific inhibition of this pathway with MLN4924 suppressed the proliferation and clonogenic survival of prostate cancer cells. Mechanistically, MLN4924 treatment inhibited cullin neddylation, inactivated Cullin-RING E3 ligases (CRLs), and led to accumulation of tumor-suppressive CRLs substrates, including cell cycle inhibitors (p21, p27, and WEE1), NF-κB signaling inhibitor IκBα, and DNA replication licensing proteins (CDT1 and ORC1). As a result, MLN4924 triggered DNA damage, G2 phase cell cycle arrest, and apoptosis. Taken together, our results demonstrate the effectiveness of targeting the neddylation pathway with MLN4924 in suppressing the growth of prostate cancer cells, implicating a potentially new therapeutic approach for the men's cancer.
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Li
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yupei
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Chunjie
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, Laboratory of Molecular Biology of Huadong Hospital affiliated to Fudan University, Shanghai 200040, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Dingwei
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Menghong
authors.initials: M
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Fu
authors.affiliation: Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Xiaomao
authors.initials: X
authors.lastname: Guo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D044842:Cullin Proteins / Q000378:metabolism*; D003517:Cyclopentanes / Q000008:administration & dosage*; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D003517:Cyclopentanes; D011743:Pyrimidines; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; C539933:pevonedistat
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