Abstract 1996
Background
Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus-1, and has a poor outcome. New molecular targets for the prevention and treatment of ATL are urgently needed. We previously reported that Sirtuin 1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylase, is highly expressed in primary acute-type ATL cells. NAD+ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) modulates Sirtuin 1 activity. Here, we examined the expression and effects of inhibiting NAMPT, a rate-limiting.
Methods
Peripheral blood mononuclear cells from ATL patients were carried out in accordance with the guidelines of the Committees for Ethical Review of Research involving Human Subjects at Kagoshima University Hospital. Cell viability was evaluated in the S1T cell line derived from an ATL patient, MT-2 cell line derived from normal human leukocytes transformed by leukemic T-cells from an ATL patient, and primary ATL cells. Animal experiments were approved by the Animal Care and Use Committee of Rakuno Gakuen University in accordance with the Guide for the Care and Use of Laboratory Animals.
Results
Peripheral blood mononuclear cells from acute-type ATL patients expressed significantly higher NAMPT protein levels than cells from healthy controls. FK866, a NAMPT inhibitor, induced apoptosis in fresh ATL cells ex vivo and HTLV-1-infected T-cell lines in vitro, which was accompanied by NAD+ depletion, activation of caspases, DNA fragmentation, and disruption of mitochondrial transmembrane potential. A pan-caspase inhibitor failed to prevent the FK866-induced cell death, while FK866 increased endonuclease G, a caspase-independent cell death mediator. Intriguingly, FK866 activated autophagy, revealed by increased LC3-II protein levels and autophagic flux. Thus, FK866 simultaneously activated apoptosis and autophagy. Finally, FK866 treatment markedly decreased human ATL tumor xenograft growth in immunodeficient mice.
Conclusions
These results demonstrate that NAMPT inhibition induces autophagy and caspase-dependent and -independent cell death in ATL cells, suggesting a novel therapeutic strategy for patients with this fatal disease.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
603 - Mendelian Randomization Study of Alzheimer's Disease and Lung Cancer
Presenter: Huaqiang Zhou
Session: Poster Display session 1
Resources:
Abstract
4462 - Spanish registry of thoracic tumors (TTR): Interim analyses of comorbidities, risk associations, personal and family history of cancer
Presenter: Rafael Lopez Castro
Session: Poster Display session 1
Resources:
Abstract
3957 - Pleural effusion TGF-beta is highly diagnostic and prognostic in malignant pleural mesothelioma
Presenter: Paul Stockhammer
Session: Poster Display session 1
Resources:
Abstract
3583 - Immune microenvironment modulation by p14/ARF in Malignant Pleural Mesothelioma
Presenter: Giulia Pasello
Session: Poster Display session 1
Resources:
Abstract
4255 - Tumor Treating Fields plus chemotherapy for first-line malignant pleural mesothelioma (MPM): radiological responses in the STELLAR trial
Presenter: Federica Grosso
Session: Poster Display session 1
Resources:
Abstract
1803 - Effects of Tumor Treating Fields (TTFields; 150 kHz) and Cisplatin or Pemetrexed Combination Therapy on Mesothelioma cells In Vitro and In Vivo
Presenter: Mijal Munster
Session: Poster Display session 1
Resources:
Abstract
2660 - Real world use of systemic therapy in elderly patients with malignant pleural mesothelioma (MPM)
Presenter: Susana Cedres
Session: Poster Display session 1
Resources:
Abstract
3150 - Pemetrexed/Cisplatin versus Gemcitabine/Cisplatin as first-line treatment for Egyptian patients with malignant pleural mesothelioma
Presenter: Mohamed Alorabi
Session: Poster Display session 1
Resources:
Abstract
4319 - Accuracy of pathologic evaluation for thymic epithelial tumors in an Italian reference Centre
Presenter: Giulia Galli
Session: Poster Display session 1
Resources:
Abstract
4811 - Comprehensive genomic profiling of thymic carcinoma in a sample Chinese population
Presenter: Baohui Han
Session: Poster Display session 1
Resources:
Abstract