PMID- 22837689
OWN - NLM
STAT- MEDLINE
DCOM- 20150812
LR  - 20220922
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 13
IP  - 6
DP  - 2012
TI  - Nec-1 enhances shikonin-induced apoptosis in leukemia cells by inhibition of 
      RIP-1 and ERK1/2.
PG  - 7212-7225
LID - 10.3390/ijms13067212 [doi]
AB  - Necrostatin-1 (Nec-1) inhibits necroptosis by allosterically inhibiting the 
      kinase activity of receptor-interacting protein 1 (RIP1), which plays a critical 
      role in necroptosis. RIP1 is a crucial adaptor kinase involved in the activation 
      of NF-kappaB, production of reactive oxygen species (ROS) and the phosphorylation of 
      mitogen activated protein kinases (MAPKs). NF-kappaB, ROS and MAPKs all play 
      important roles in apoptotic signaling. Nec-1 was regarded as having no effect on 
      apoptosis. Here, we report that Nec-1 increased the rate of nuclear condensation 
      and caspases activation induced by a low concentration of shikonin (SHK) in HL60, 
      K562 and primary leukemia cells. siRNA-mediated knockdown of RIP1 significantly 
      enhanced shikonin-induced apoptosis in K562 and HL60 cells. Shikonin treatment 
      alone could slightly inhibit the phosphorylation of ERK1/2 in leukemia cells, and 
      the inhibitory effect on ERK1/2 was significantly augmented by Nec-1. We also 
      found that Nec-1 could inhibit NF-kappaB p65 translocation to the nucleus at a later 
      stage of SHK treatment. In conclusion, we found that Nec-1 can promote 
      shikonin-induced apoptosis in leukemia cells. The mechanism by which Nec-1 
      sensitizes shikonin-induced apoptosis appears to be the inhibition of RIP1 
      kinase-dependent phosphorylation of ERK1/2. To our knowledge, this is the first 
      study to document Nec-1 sensitizes cancer cells to apoptosis.
FAU - Han, Weidong
AU  - Han W
AD  - Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University 
      School of Medicine, 3 East Qingchun Road, Hangzhou 310016, China.
FAU - Xie, Jiansheng
AU  - Xie J
AD  - The Cancer Institute, The Second Affiliated Hospital, Zhejiang University School 
      of Medicine, 88 Jiefang Road, Hangzhou 310009, China.
FAU - Fang, Yong
AU  - Fang Y
AD  - Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University 
      School of Medicine, 3 East Qingchun Road, Hangzhou 310016, China.
FAU - Wang, Zhanggui
AU  - Wang Z
AD  - Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University 
      School of Medicine, 3 East Qingchun Road, Hangzhou 310016, China.
FAU - Pan, Hongming
AU  - Pan H
AD  - Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University 
      School of Medicine, 3 East Qingchun Road, Hangzhou 310016, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120612
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (AGFG1 protein, human)
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Naphthoquinones)
RN  - 0 (Nuclear Pore Complex Proteins)
RN  - 0 (RELA protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (necrostatin-1)
RN  - 3IK6592UBW (shikonin)
RN  - EC 2.7.11.24 (MAPK1 protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Active Transport, Cell Nucleus/drug effects/genetics
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Apoptosis/*drug effects/genetics
MH  - Cell Nucleus/genetics/metabolism/pathology
MH  - HL-60 Cells
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Indoles/*pharmacology
MH  - K562 Cells
MH  - Leukemia/genetics/*metabolism/pathology
MH  - MAP Kinase Signaling System/drug effects/genetics
MH  - Mitogen-Activated Protein Kinase 1/genetics/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/genetics/*metabolism
MH  - Naphthoquinones/*pharmacology
MH  - Nuclear Pore Complex Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - RNA-Binding Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Transcription Factor RelA/genetics/metabolism
PMC - PMC3397521
OTO - NOTNLM
OT  - ERK1/2
OT  - Necrostatin-1
OT  - apoptosis
OT  - receptor-interacting protein 1
OT  - shikonin
EDAT- 2012/07/28 06:00
MHDA- 2012/07/28 06:01
PMCR- 2012/01/01
CRDT- 2012/07/28 06:00
PHST- 2012/03/31 00:00 [received]
PHST- 2012/04/23 00:00 [revised]
PHST- 2012/06/07 00:00 [accepted]
PHST- 2012/07/28 06:00 [entrez]
PHST- 2012/07/28 06:00 [pubmed]
PHST- 2012/07/28 06:01 [medline]
PHST- 2012/01/01 00:00 [pmc-release]
AID - ijms13067212 [pii]
AID - ijms-13-07212 [pii]
AID - 10.3390/ijms13067212 [doi]
PST - ppublish
SO  - Int J Mol Sci. 2012;13(6):7212-7225. doi: 10.3390/ijms13067212. Epub 2012 Jun 12.