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Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma.
Ferguson, Ian D; Lin, Yu-Hsiu T; Lam, Christine; Shao, Hao; Tharp, Kevin M; Hale, Martina; Kasap, Corynn; Mariano, Margarette C; Kishishita, Audrey; Patiño Escobar, Bonell; Mandal, Kamal; Steri, Veronica; Wang, Donghui; Phojanakong, Paul; Tuomivaara, Sami T; Hann, Byron; Driessen, Christoph; Van Ness, Brian; Gestwicki, Jason E; Wiita, Arun P.
Afiliação
  • Ferguson ID; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Lin YT; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Lam C; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Shao H; Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Tharp KM; Department of Surgery, University of California, San Francisco, San Francisco CA 94143, USA.
  • Hale M; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Kasap C; Department of Medicine, Division of Hematology or Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Mariano MC; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Kishishita A; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA; Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Patiño Escobar B; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Mandal K; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Steri V; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Wang D; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Phojanakong P; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Tuomivaara ST; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
  • Hann B; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Driessen C; Department of Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
  • Van Ness B; Department of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN 55455, USA.
  • Gestwicki JE; Institute for Neurodegenerative Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Wiita AP; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA. Electronic address: arun.wiita@ucsf.edu.
Cell Chem Biol ; 29(8): 1288-1302.e7, 2022 08 18.
Article em En | MEDLINE | ID: mdl-35853457
ABSTRACT
Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma cells overcoming PI-induced stress. We therefore explored allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. JG compounds exhibited increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Shotgun and pulsed SILAC mass spectrometry demonstrated that JGs unexpectedly impact myeloma proteostasis by destabilizing the 55S mitoribosome. Our data suggest JGs have the most pronounced anti-myeloma effect not through inhibiting cytosolic HSP70 proteins but instead through mitochondrial-localized HSP70, HSPA9/mortalin. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mieloma Múltiplo / Antineoplásicos Limite: Humans Idioma: En Revista: Cell Chem Biol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Mieloma Múltiplo / Antineoplásicos Limite: Humans Idioma: En Revista: Cell Chem Biol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos