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Inhibitory effect of a neddylation blockade on HTLV-1-infected T cells via modulation of NF-κB, AP-1, and Akt signaling.
- Source :
-
Leukemia & Lymphoma . Jul2024, Vol. 65 Issue 7, p978-988. 11p. - Publication Year :
- 2024
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10428194
- Volume :
- 65
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- Leukemia & Lymphoma
- Publication Type :
- Academic Journal
- Accession number :
- 178176880
- Full Text :
- https://doi.org/10.1080/10428194.2024.2328219