Your browser doesn't support javascript.
loading
Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer.
Xu, Pengfei; Yang, Joy C; Chen, Bo; Ning, Shu; Zhang, Xiong; Wang, Leyi; Nip, Christopher; Shen, Yuqiu; Johnson, Oleta T; Grigorean, Gabriela; Phinney, Brett; Liu, Liangren; Wei, Qiang; Corey, Eva; Tepper, Clifford G; Chen, Hong-Wu; Evans, Christopher P; Dall'Era, Marc A; Gao, Allen C; Gestwicki, Jason E; Liu, Chengfei.
Afiliação
  • Xu P; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Yang JC; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Chen B; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Ning S; Department of Urology, West China Hospital, Sichuan University, Sichuan, China.
  • Zhang X; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Wang L; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
  • Nip C; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Shen Y; Graduate Group in Integrative Pathobiology, University of California, Davis, CA, USA.
  • Johnson OT; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Grigorean G; Department of Urologic Surgery, University of California, Davis, CA, USA.
  • Phinney B; Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
  • Liu L; Proteomics Core Facility, University of California, Davis, CA, USA.
  • Wei Q; Proteomics Core Facility, University of California, Davis, CA, USA.
  • Corey E; Department of Urology, West China Hospital, Sichuan University, Sichuan, China.
  • Tepper CG; Department of Urology, West China Hospital, Sichuan University, Sichuan, China.
  • Chen HW; Department of Urology, University of Washington, Washington, WA, USA.
  • Evans CP; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
  • Dall'Era MA; University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA.
  • Gao AC; Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA.
  • Gestwicki JE; University of California, Davis Comprehensive Cancer Center, Sacramento, CA, USA.
  • Liu C; Department of Urologic Surgery, University of California, Davis, CA, USA.
Nat Commun ; 15(1): 6626, 2024 Aug 05.
Article em En | MEDLINE | ID: mdl-39103353
ABSTRACT
N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved "SELILKR" motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70's dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Proteínas de Choque Térmico HSP70 / Ubiquitina-Proteína Ligases / Ubiquitinação / Proteostase Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Proteínas de Choque Térmico HSP70 / Ubiquitina-Proteína Ligases / Ubiquitinação / Proteostase Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article