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Strategic Suppression of Nicotinamide Phosphoribosyl Transferase for Uterine Leiomyoma Progression Modulation
34 Pages Posted: 30 May 2024
More...Abstract
Background: Uterine Leiomyoma (UL) is marked by heightened cell proliferation, extracellular matrix (ECM) accumulation, and stemness. Elevated levels of nicotinamide phosphoribosyltransferase (NAMPT) may modulate nicotinamide adenine dinucleotide (NAD) metabolism, presenting a novel therapeutic opportunity.
Methods: NAMPT expression was analyzed in human UL patient tissue and its correlation with ECM and stemness markers was evaluated. Protein-protein interactions were studied to understand NAMPT's role in UL. The effects of a NAMPT inhibitor on UL cell survival and stemness were assessed. Additionally, siNAMPT silencing was used to study the reduction of ECM-related proteins targeted by NAMPT. The role of lysosome function homeostasis and phagophore formation in ECM accumulation was also explored.
Findings: Increased NAMPT expression was observed in human UL patient tissues, which positively correlated with ECM and stemness markers. Utilizing a NAMPT inhibitor significantly suppressed UL cell survival and stemness progression. Silencing NAMPT with siNAMPT led to a reduction in ECM-related proteins critical for UL progression. Maintaining lysosome function homeostasis and disrupting phagophore formation, activated by NAMPT inhibition, effectively abolished ECM accumulation.
Interpretation: Our study highlights the pivotal role of NAMPT in UL progression. Inhibition of NAMPT, through agents such as FK866 and NAM, shows promise in restraining UL progression. These findings suggest a new therapeutic avenue targeting NAMPT, which is pathophysiologically involved in UL patients.\
Funding: This study was supported by the grants (MOST109-2314-B-038-059, MOST109-2628-B-038-015, MOST109-2628-B-038-015, MOST110-2314-B-038-158, MOST110-2628-B-038-018 and MOST110-) from the Ministry of Science and Technology, Taiwan.
Declaration of Interest: The authors have declared no conflict of interest.
Ethical Approval: Human tissues were obtained from 30–45 year-old women (n = 9) who had received myomectomy treatment at the Department of Oncology, Taipei Medical University Hospital (Taipei, Taiwan). The study was approved by the Institutional Review Board and Ethics Committee of Taipei Medical University Hospital (Permit Number: N202305018). The animal studies were conducted according to the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Taipei Medical University (No.: LAC-2019-0535).
Keywords: Uterine leiomyoma, NAMPT, NAD, ECM
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