PMID- 30423551
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20191210
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Linking)
VI  - 50
IP  - 6
DP  - 2018
TI  - Constitutively Photomorphogenic 1 Reduces the Sensitivity of Chronic Lymphocytic 
      Leukemia Cells to Fludarabine Through Promotion of Ubiquitin-Mediated P53 
      Degradation.
PG  - 2314-2328
LID - 10.1159/000495092 [doi]
AB  - BACKGROUND/AIMS: Chronic Lymphocytic leukemia (CLL) is characterized by 
      accumulation of cells in the G0/G1 phase of the cell cycle and resistance to 
      apoptosis due to gene mutation or abnormal gene expression. In our previous 
      study, constitutively photomorphogenic 1 (COP1) was shown to be upregulated in 
      Binet C-phase CLL patients. Based on the negative regulation of COP1 in the 
      repair of DNA damage, we further studied the function of COP1 in CLL cell 
      apoptosis induced by fludarabine in vitro and in vivo. METHODS: We analyzed the 
      sensitivity of primary CLL cells to the fludarabine by CCK-8, and detected the 
      expression of p53 in cells after drug treatment by western blot. Next, we 
      constructed COP1 overexrpessing CLL cell line HG3, and analyzed the effect of 
      COP1 overexpression on the HG3 cell's apoptosis, and HG3 transplant mice survival 
      with drug treatment. RESULTS: Here, we found that primary CLL cells with high 
      expression of COP1 showed low sensitivity to the drug and presented delayed 
      enrichment of p53 protein than cells with low COP1 expressed. COP1 overexpression 
      reduced HG3 cell sensitivity to the fludarabine treatment and inhibited cell 
      apoptosis, and also retarded itself via autoubiquitination. The further study 
      showed that COP1 promoted ubiquitin-dependent p53 degradation, which further 
      disrupts the formation of the p53-Brn-3a complex and activation of Bcl-2 
      transcription. Moreover, mice engrafted with cells overexpressing COP1 showed a 
      shortened survival, increased tumor cells burden in spleen and bone marrow (BM), 
      and reduced tumor cell apoptosis even when fludarabine combined cyclophosphamide 
      (F+C) therapy was administered. CONCLUSION: This study demonstrates that COP1 
      contributes to drug resistance of CLL cells to the fludarabine treatment in vitro 
      and in vivo.
CI  - (c) 2018 The Author(s). Published by S. Karger AG, Basel.
FAU - Fu, Chunling
AU  - Fu C
AD  - Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, China.
FAU - Shi, Xuanxuan
AU  - Shi X
AD  - Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
FAU - Gong, Yanqing
AU  - Gong Y
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, China.
FAU - Wan, Yan
AU  - Wan Y
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, China.
FAU - Sun, Zengtian
AU  - Sun Z
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, China.
FAU - Shi, Hengliang
AU  - Shi H
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, China.
FAU - Wang, Zhenzhen
AU  - Wang Z
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, China.
FAU - Marinaccio, Christian
AU  - Marinaccio C
AD  - Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA.
FAU - Crispino, John D
AU  - Crispino JD
AD  - Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA.
FAU - Xu, Kailin
AU  - Xu K
AD  - Blood Diseases Institute, Xuzhou Medical University, Xuzhou, ChinaLihmd@163.com.
AD  - Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, ChinaLihmd@163.com.
LA  - eng
PT  - Journal Article
DEP - 20181113
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Transcription Factor Brn-3A)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - EC 2.3.2.27 (COP1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - FA2DM6879K (Vidarabine)
RN  - P2K93U8740 (fludarabine)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/*drug effects
MH  - Bone Marrow/pathology
MH  - Cell Line, Tumor
MH  - Cyclophosphamide/pharmacology/therapeutic use
MH  - Female
MH  - Humans
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality/*pathology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Promoter Regions, Genetic
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - Spleen/pathology
MH  - Survival Rate
MH  - Transcription Factor Brn-3A/metabolism
MH  - Tumor Suppressor Protein p53/*metabolism
MH  - Ubiquitin-Protein Ligases/genetics/*metabolism
MH  - Ubiquitination
MH  - Vidarabine/*analogs & derivatives/pharmacology/therapeutic use
OTO - NOTNLM
OT  - Apoptosis
OT  - COP1
OT  - Cll
OT  - F+C therapy
OT  - Ubiquitin-dependent degradation
EDAT- 2018/11/14 06:00
MHDA- 2018/12/12 06:00
CRDT- 2018/11/14 06:00
PHST- 2018/01/31 00:00 [received]
PHST- 2018/11/05 00:00 [accepted]
PHST- 2018/11/14 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2018/11/14 06:00 [entrez]
AID - 000495092 [pii]
AID - 10.1159/000495092 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2018;50(6):2314-2328. doi: 10.1159/000495092. Epub 2018 Nov 
      13.