PMID- 33007289
OWN - NLM
STAT- MEDLINE
DCOM- 20201211
LR  - 20201214
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
VI  - 332
DP  - 2020 Dec 1
TI  - Molecular mechanisms underlying the effects of the small molecule AMC-04 on 
      apoptosis: Roles of the activating transcription factor 4-C/EBP homologous 
      protein-death receptor 5 pathway.
PG  - 109277
LID - S0009-2797(20)31155-8 [pii]
LID - 10.1016/j.cbi.2020.109277 [doi]
AB  - The unfolded protein response (UPR) is an emerging target pathway for cancer 
      treatment owing to its ability to induce cell death. In our previous analysis of 
      UPR-modulating small molecules, we had reported that piperazine oxalate 
      derivative compounds (AMC-01-04) are able to promote increased phosphorylation of 
      eukaryotic translation initiation factor-2 alpha (eIF2alpha). In this study, we found 
      that AMC-04 induces apoptotic cell death via the activation of UPR in human 
      breast and liver cancer cells. AMC-04 upregulated the expression of activating 
      transcription factor-4 (ATF4)-C/EBP homologous protein (CHOP) and death receptor 
      5 (DR5) in cancer cells, as revealed by microarray analysis, small-interference 
      RNA assay, and western blotting. From a mechanistic perspective, cytotoxic UPR 
      pathway activation by AMC-04 is mediated by reactive oxygen species (ROS) and p38 
      mitogen-activated protein kinase (p38 MAPK) signaling. A chemical informatics 
      approach predicted that AMC-04 modulates histone methyltransferase activity. 
      Based on biochemical analysis, the activity of histone methyltransferases, 
      including SUV39H1, SUV39H2, SETDB1, and EHMT1, was inhibited by AMC-04. 
      Furthermore, chemical inhibition of the identified target proteins induced UPR 
      activation and apoptotic cell death, suggesting that inhibition of histone 
      methyltransferases is a promising strategy for cancer therapy. Taken together, we 
      showed that the small molecule AMC-04 modulates epigenetic enzyme activity and 
      mediates the link between cytotoxic UPR and histone modifications.
CI  - Copyright (c) 2020 Elsevier B.V. All rights reserved.
FAU - Kim, So Young
AU  - Kim SY
AD  - Biomedical Research Center, ASAN Institute for Life Sciences, ASAN Medical 
      Center, Seoul, 05505, Republic of Korea.
FAU - Hwang, Supyong
AU  - Hwang S
AD  - Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, 
      ASAN Medical Center, Seoul, 05505, Republic of Korea.
FAU - Choi, Min Kyung
AU  - Choi MK
AD  - Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, 
      ASAN Medical Center, Seoul, 05505, Republic of Korea.
FAU - Park, Sojung
AU  - Park S
AD  - Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, 
      ASAN Medical Center, Seoul, 05505, Republic of Korea.
FAU - Nam, Ky Youb
AU  - Nam KY
AD  - Pharosibio, Heungan Daero 427, Anyang, Gyeonggido, Republic of Korea. Electronic 
      address: kyn@pharosibio.com.
FAU - Kim, Inki
AU  - Kim I
AD  - Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, 
      ASAN Medical Center, Seoul, 05505, Republic of Korea; Department of Convergence 
      Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of 
      Korea. Electronic address: ik.kim@amc.seoul.kr.
LA  - eng
PT  - Journal Article
DEP - 20200929
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Small Molecule Libraries)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.1.1.- (Histone Methyltransferases)
SB  - IM
MH  - Activating Transcription Factor 4/*metabolism
MH  - Apoptosis/*drug effects
MH  - Cell Line, Tumor
MH  - Endoplasmic Reticulum Stress/drug effects/genetics
MH  - Enzyme Inhibitors/pharmacology
MH  - Histone Methyltransferases/antagonists & inhibitors/metabolism
MH  - Humans
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism
MH  - *Signal Transduction/drug effects
MH  - Small Molecule Libraries/chemistry/*pharmacology
MH  - Transcription Factor CHOP/*metabolism
MH  - Unfolded Protein Response/drug effects/genetics
MH  - Up-Regulation/drug effects/genetics
OTO - NOTNLM
OT  - C/EBP homologous Protein
OT  - Death receptor-5
OT  - Histone methyl transferase
OT  - Human cancer cell
OT  - Reactive oxygen species
OT  - Unfolded protein response
EDAT- 2020/10/03 06:00
MHDA- 2020/12/15 06:00
CRDT- 2020/10/02 20:09
PHST- 2020/07/03 00:00 [received]
PHST- 2020/08/31 00:00 [revised]
PHST- 2020/09/28 00:00 [accepted]
PHST- 2020/10/03 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/10/02 20:09 [entrez]
AID - S0009-2797(20)31155-8 [pii]
AID - 10.1016/j.cbi.2020.109277 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2020 Dec 1;332:109277. doi: 10.1016/j.cbi.2020.109277. Epub 
      2020 Sep 29.