Inhibitory effect of a neddylation blockade on HTLV-1-infected T cells via modulation of NF-κB, AP-1, and Akt signaling.
Leuk Lymphoma
; 65(7): 978-988, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38489672
ABSTRACT
Adult T-cell leukemia (ATL), caused by HTLV-1, is the most lethal hematological malignancy. NEDD8-activating enzyme (NAE) is a component of the NEDD8 conjunction pathway that regulates cullin-RING ubiquitin ligase (CRL) activity. HTLV-1-infected T cells expressed higher levels of NAE catalytic subunit UBA3 than normal peripheral blood mononuclear cells. NAE1 knockdown inhibited proliferation of HTLV-1-infected T cells. The NAE1 inhibitor MLN4924 suppressed neddylation of cullin and inhibited the CRL-mediated turnover of tumor suppressor proteins. MLN4924 inhibited proliferation of HTLV-1-infected T cells by inducing DNA damage, leading to S phase arrest and caspase-dependent apoptosis. S phase arrest was associated with CDK2 and cyclin A downregulation. MLN4924-induced apoptosis was mediated by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, MLN4924 inhibited NF-κB, AP-1, and Akt signaling pathways and activated JNK. Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Human T-lymphotropic virus 1
/
Signal Transduction
/
NF-kappa B
/
Apoptosis
/
Transcription Factor AP-1
/
Cyclopentanes
/
Ubiquitin-Activating Enzymes
/
Cell Proliferation
/
Proto-Oncogene Proteins c-akt
Limits:
Humans
Language:
En
Journal:
Leuk Lymphoma
Journal subject:
HEMATOLOGIA
/
NEOPLASIAS
Year:
2024
Document type:
Article
Affiliation country:
Japón