Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells

E. J. Born, S. V. Hartman, Sarah A Holstein

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways.

Original languageEnglish (US)
Article numbere167
JournalBlood Cancer Journal
Volume3
Issue number12
DOIs
StatePublished - Dec 1 2013

Fingerprint

HSP90 Heat-Shock Proteins
Unfolded Protein Response
Protein Transport
Biosynthetic Pathways
Terpenes
Apoptosis
Cell Death
tanespimycin
Prenylation
Protein Unfolding
Proteins
Protein Folding
Heat-Shock Proteins
Multiple Myeloma
Amyloid
Light

Keywords

  • HSP90
  • Rab
  • amyloid
  • multiple myeloma
  • unfolded protein response pathway

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells. / Born, E. J.; Hartman, S. V.; Holstein, Sarah A.

In: Blood Cancer Journal, Vol. 3, No. 12, e167, 01.12.2013.

Research output: Contribution to journalArticle

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