Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8
T cell
breast cancer
cancer stem cell
epithelial-to-mesenchymal transition
immunotherapy
melanoma
metastasis
nuclear translocation
protein kinase C (PKC)-θ
resistance
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
21 Mar 2022
21 Mar 2022
Historique:
received:
08
02
2022
revised:
07
03
2022
accepted:
14
03
2022
entrez:
25
3
2022
pubmed:
26
3
2022
medline:
26
3
2022
Statut:
epublish
Résumé
Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8
Identifiants
pubmed: 35326747
pii: cancers14061596
doi: 10.3390/cancers14061596
pmc: PMC8946217
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : National Health and Medical Research Council
ID : GNT1105409
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