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Inhibition of N-myristoyltransferase activity promotes androgen receptor degradation in prostate cancer.
Alsaidan, Omar Awad; Onobun, Emmanuel; Ye, Chenming; Lou, Lei; Beharry, Zanna; Xie, Zhong-Ru; Lebedyeva, Iryna; Crich, David; Cai, Houjian.
Afiliación
  • Alsaidan OA; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia Athens, Athens, Georgia, USA.
  • Onobun E; Department of Chemistry, Franklin College of Arts and Sciences, University of Georgia Athens, Athens, Georgia, USA.
  • Ye C; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia Athens, Athens, Georgia, USA.
  • Lou L; School of Electrical and Computer Engineering, College of Engineering, University of Georgia Athens, Athens, Georgia, USA.
  • Beharry Z; Department of Chemical and Physical Sciences, University of the Virgin Islands, Saint Thomas, Virgin Islands, USA.
  • Xie ZR; School of Electrical and Computer Engineering, College of Engineering, University of Georgia Athens, Athens, Georgia, USA.
  • Lebedyeva I; Department of Chemistry and Physics, Augusta University, Augusta, Georgia, USA.
  • Crich D; Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia Athens, Athens, Georgia, USA.
  • Cai H; Department of Chemistry, Franklin College of Arts and Sciences, University of Georgia Athens, Athens, Georgia, USA.
Prostate ; 84(3): 254-268, 2024 Feb.
Article en En | MEDLINE | ID: mdl-37905842
BACKGROUND: Even though prostate cancer (PCa) patients initially respond to androgen deprivation therapy, some will eventually develop castration resistant prostate cancer (CRPC). Androgen receptor (AR) mediated cell signaling is a major driver in the progression of CRPC while only a fraction of PCa becomes AR negative. This study aimed to understand the regulation of AR levels by N-myristoyltransferase in PCa cells. METHODS: Two enantiomers, (1S,2S)- d-NMAPPD and (1R,2R)- d-NMAPPD (LCL4), were characterized by various methods (1 H and 13 C NMR, UHPLC, high-resolution mass spectra, circular dichroism) and evaluated for the ability to bind to N-myristoyltransferase 1 (NMT1) using computational docking analysis. structure-activity relationship analysis of these compounds led to the synthesis of (1R,2R)-LCL204 and evaluation as a potential NMT1 inhibitor utilizing the purified full length NMT1 enzyme. The NMT inhibitory activity wase determined by Click chemistry and immunoblotting. Regulation of NMT1 on tumor growth was evaluated in a xenograft tumor model. RESULTS: (1R,2R)- d-NMAPPD, but not its enantiomer (1S,2S)- d-NMAPPD, inhibited NMT1 activity and reduced AR protein levels. (1R,2R)-LCL204, a derivative of (1R,2R)- d-NMAPPD, inhibited global protein myristoylation. It also suppressed protein levels, nuclear translocation, and transcriptional activity of AR full-length or variants in PCa cells. This was due to enhanced ubiquitin and proteasome-mediated degradation of AR. Knockdown of NMT1 levels inhibited tumor growth and proliferation of cancer cells. CONCLUSION: Inhibitory efficacy on N-myristoyltransferase activity by d-NMAPPD is stereospecific. (1R,2R)-LCL204 reduced global N-myristoylation and androgen receptor protein levels at low micromolar concentrations in prostate cancer cells. pharmacological inhibition of NMT1 enhances ubiquitin-mediated proteasome degradation of AR. This study illustrates a novel function of N-myristoyltransferase and provides a potential strategy for treatment of CRPC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Neoplasias de la Próstata Resistentes a la Castración Límite: Humans / Male Idioma: En Revista: Prostate Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Neoplasias de la Próstata Resistentes a la Castración Límite: Humans / Male Idioma: En Revista: Prostate Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos