Inhibition of protein kinase C delta leads to cellular senescence to induce anti-tumor effects in colorectal cancer.
cellular senescence
colorectal cancer
kinase inhibitor
protein kinase C delta
tumorigenesis
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
revised:
10
02
2023
received:
17
10
2022
accepted:
21
02
2023
medline:
5
6
2023
pubmed:
1
3
2023
entrez:
28
2
2023
Statut:
ppublish
Résumé
Protein kinase C delta (PKCδ) is a multifunctional serine-threonine kinase implicated in cell proliferation, differentiation, tumorigenesis, and therapeutic resistance. However, the molecular mechanism of PKCδ in colorectal cancer (CRC) remains unclear. In this study, we showed that PKCδ acts as a negative regulator of cellular senescence in p53 wild-type (wt-p53) CRC. Immunohistochemical analysis revealed that PKCδ levels in human CRC tissues were higher than those in the surrounding normal tissues. Deletion studies have shown that cell proliferation and tumorigenesis in wt-p53 CRC is sensitive to PKCδ expression. We found that PKCδ activates p21 via a p53-independent pathway and that PKCδ-kinase activity is essential for p21 activity. In addition, both repression of PKCδ expression and inhibition of PKCδ activity induced cellular senescence-like phenotypes, including increased senescence-associated β-galactosidase (SA-β-gal) staining, low LaminB1 expression, large nucleus size, and senescence-associated secretory phenotype (SASP) detection. Finally, a kinase inhibitor of PKCδ suppressed senescence-dependent tumorigenicity in a dose-dependent manner. These results offer a mechanistic insight into CRC survival and tumorigenesis. In addition, a novel therapeutic strategy for wt-p53 CRC is proposed.
Identifiants
pubmed: 36851883
doi: 10.1111/cas.15768
pmc: PMC10236638
doi:
Substances chimiques
Protein Kinase C-delta
EC 2.7.11.13
Tumor Suppressor Protein p53
0
Cyclin-Dependent Kinase Inhibitor p21
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2471-2484Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP16K18434
Organisme : Japan Society for the Promotion of Science
ID : JP17H03584
Organisme : Japan Society for the Promotion of Science
ID : JP18K15253
Organisme : Japan Society for the Promotion of Science
ID : JP18K19484
Organisme : Japan Society for the Promotion of Science
ID : JP20H03519
Organisme : Japan Society for the Promotion of Science
ID : JP20K07621
Informations de copyright
© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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