A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.
CP2c complex disruption
a cell-penetrant peptide
pan-anticancer drug
synthetic lethality
transcription factor CP2c
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
23
09
2023
received:
25
07
2023
medline:
27
11
2023
pubmed:
17
10
2023
entrez:
16
10
2023
Statut:
ppublish
Résumé
Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.
Identifiants
pubmed: 37845006
doi: 10.1002/advs.202305096
pmc: PMC10667816
doi:
Substances chimiques
DNA-Binding Proteins
0
Transcription Factors
0
Peptides
0
TDP2 protein, human
EC 3.1.4.-
Phosphoric Diester Hydrolases
EC 3.1.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2305096Subventions
Organisme : National Research Foundation of Korea, Bio & Medical Technology Development
ID : NRF-2017M3A9C8027975
Organisme : National Research Foundation of Korea, Basic Science Research Program
ID : 2010-0025223
Organisme : National Research Foundation of Korea, Basic Science Research Program
ID : 2014R1A2A1A11054432
Organisme : National Research Foundation of Korea, Basic Science Research Program
ID : NRF-2020R1A2C2009112
Informations de copyright
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
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