PMID- 37301315
OWN - NLM
STAT- MEDLINE
DCOM- 20230728
LR  - 20230928
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 109
DP  - 2023 Sep
TI  - Repurposing a plant alkaloid homoharringtonine targets insulinoma associated-1 in 
      N-Myc-activated neuroblastoma.
PG  - 110753
LID - S0898-6568(23)00167-5 [pii]
LID - 10.1016/j.cellsig.2023.110753 [doi]
AB  - High-risk neuroblastoma (NB) is a heterogeneous and malignant childhood cancer 
      that is frequently characterized by MYCN proto-oncogene amplification or elevated 
      N-Myc protein (N-Myc) expression. An N-Myc downstream target gene, insulinoma 
      associated-1 (INSM1) has emerged as a biomarker that plays a critical role in 
      facilitating NB tumor cell growth and transformation. N-Myc activates endogenous 
      INSM1 gene expression through binding to the E2-box of the INSM1 proximal 
      promoter in NB. We identified a plant alkaloid, homoharringtonine (HHT), from a 
      chemical library screening showing potent inhibition of INSM1 promoter activity. 
      This positive-hit plant alkaloid exemplifies an effective screening approach for 
      repurposed compound targeting INSM1 expression in NB cancer therapy. The elevated 
      N-Myc and INSM1 expression in NB constitutes a positive-loop through INSM1 
      activation that promotes N-Myc stability. In the present study, the biological 
      effects and anti-tumor properties of HHT against NB were examined. HHT either 
      down regulates and/or interferes with the binding of N-Myc to the E2-box of the 
      INSM1 promoter and the inhibition of PI3K/AKT-mediated N-Myc stability could lead 
      to the NB cell apoptosis. HHT inhibition of NB cell proliferation is consistent 
      with the INSM1 expression as higher level of INSM1 exhibits a more sensitive 
      IC(50) value. The combination treatment of HHT and A674563 provides a better 
      option of increasing potency and reducing cellular cytotoxicity than HHT or 
      A674563 treatment alone. Taken together, the suppression of the INSM1-associated 
      signaling pathway axis promotes the inhibition of NB tumor cell growth. This 
      study developed a feasible approach for repurposing an effective anti-NB drug.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Chen, Chiachen
AU  - Chen C
AD  - Department of Genetics, Louisiana State University Health Sciences Center, 533 
      Bolivar St. CSRB, New Orleans, LA 70112, USA.
FAU - Wu, Jiande
AU  - Wu J
AD  - Department of Genetics, Louisiana State University Health Sciences Center, 533 
      Bolivar St. CSRB, New Orleans, LA 70112, USA; Bioinformatics and Genomics 
      Program, 533 Bolivar St. CSRB, Louisiana State University Health Sciences Center, 
      New Orleans, LA 70112, USA.
FAU - Hicks, Chindo
AU  - Hicks C
AD  - Department of Genetics, Louisiana State University Health Sciences Center, 533 
      Bolivar St. CSRB, New Orleans, LA 70112, USA; Bioinformatics and Genomics 
      Program, 533 Bolivar St. CSRB, Louisiana State University Health Sciences Center, 
      New Orleans, LA 70112, USA.
FAU - Lan, Michael S
AU  - Lan MS
AD  - Department of Genetics, Louisiana State University Health Sciences Center, 533 
      Bolivar St. CSRB, New Orleans, LA 70112, USA. Electronic address: 
      mlan@lsuhsc.edu.
LA  - eng
GR  - R21 CA218764/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230609
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 6FG8041S5B (Homoharringtonine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 147955-03-1 (INSM1 protein, human)
RN  - 0 (Repressor Proteins)
SB  - IM
MH  - Humans
MH  - Child
MH  - Homoharringtonine
MH  - *Insulinoma
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Drug Repositioning
MH  - Cell Line, Tumor
MH  - *Neuroblastoma/genetics
MH  - *Pancreatic Neoplasms/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Repressor Proteins/metabolism
PMC - PMC10527743
MID - NIHMS1907974
OTO - NOTNLM
OT  - Alkaloid
OT  - Homoharringtonine
OT  - INSM1
OT  - MYCN proto-oncogene
OT  - Neuroblastoma
COIS- Declaration of Competing Interest The authors declare that they have no conflicts 
      of interest with the contents of this article.
EDAT- 2023/06/11 01:06
MHDA- 2023/07/28 06:42
PMCR- 2024/09/01
CRDT- 2023/06/10 19:26
PHST- 2023/05/04 00:00 [received]
PHST- 2023/05/30 00:00 [revised]
PHST- 2023/06/05 00:00 [accepted]
PHST- 2024/09/01 00:00 [pmc-release]
PHST- 2023/07/28 06:42 [medline]
PHST- 2023/06/11 01:06 [pubmed]
PHST- 2023/06/10 19:26 [entrez]
AID - S0898-6568(23)00167-5 [pii]
AID - 10.1016/j.cellsig.2023.110753 [doi]
PST - ppublish
SO  - Cell Signal. 2023 Sep;109:110753. doi: 10.1016/j.cellsig.2023.110753. Epub 2023 
      Jun 9.