TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.
Ataxia Telangiectasia Mutated (ATM) kinase
DNA Damage Response (DDR)
DNA-dependent protein kinase catalytic subunit (DNA-PKcs)
Head and Neck Squamous Cell Carcinoma (HNSCC)
Interactomics
Nucleosomal histones
PP2A
PP2A-like phosphatases
PP4
PP6
Proteomics
Rad51 recombinase
Radioresistance
Target of rapamycin signaling pathway regulator-like 1 (TIPRL1)
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
16 Nov 2023
16 Nov 2023
Historique:
accepted:
23
10
2023
medline:
17
11
2023
pubmed:
17
11
2023
entrez:
16
11
2023
Statut:
aheadofprint
Résumé
TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 - all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC). TIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells. TIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A non-phospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation. Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.
Identifiants
pubmed: 37971644
doi: 10.1007/s13402-023-00895-6
pii: 10.1007/s13402-023-00895-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Onderzoeksraad, KU Leuven
ID : C24/17/073
Organisme : Onderzoeksraad, KU Leuven
ID : C24/17/073
Organisme : Onderzoeksraad, KU Leuven
ID : C24/17/073
Organisme : Onderzoeksraad, KU Leuven
ID : C24/17/073
Organisme : Onderzoeksraad, KU Leuven
ID : C24/17/073
Organisme : Onderzoeksraad, KU Leuven
ID : C24/17/073
Informations de copyright
© 2023. Springer Nature Switzerland AG.
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