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Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells

Esther A Obeng1, Louise M Carlson, Delia M Gutman

  • 1Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.

Blood
|March 2, 2006
PubMed

Insights

Proteasome inhibitors (PIs) induce apoptosis in multiple myeloma (MM) cells by initiating the unfolded protein response (UPR). MM cells

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Multiple myeloma (MM) is an incurable plasma cell malignancy.
  • Bortezomib, a proteasome inhibitor (PI), induces apoptosis in MM cells, but its selectivity mechanism is unclear.
  • MM cells are characterized by high protein secretion, involving the endoplasmic reticulum (ER).

Purpose of the Study:

  • To investigate the mechanism of bortezomib-induced apoptosis in MM cells.
  • To explore the role of the unfolded protein response (UPR) in MM cell sensitivity to PIs.
  • To determine if MM cells' secretory function influences their response to PIs.

Main Methods:

  • Compared sensitivity of MM cell lines to different PIs and NF-kappaB inhibition.
  • Analyzed the induction of UPR components (PERK, ATF4, CHOP) following PI treatment.
  • Correlated MM cell sensitivity to PIs with the levels of retained immunoglobulin subunits in the ER.

Main Results:

  • MM cell lines showed similar sensitivity to PIs but varied in response to NF-kappaB inhibition.
  • PIs induced the UPR, leading to the accumulation of misfolded proteins in the ER.
  • Bortezomib treatment rapidly induced pro-apoptotic UPR components (PERK, ATF4, CHOP).
  • Higher levels of retained immunoglobulin subunits correlated with increased sensitivity to PIs.
  • MM cells constitutively express ER chaperones (GRP78/Bip, GRP94/gp96), suggesting a role in secretory function and UPR modulation.

Conclusions:

  • MM cells possess a lower threshold for ER stress-induced apoptosis due to their inherent secretory functions and constitutive expression of UPR survival factors.
  • PIs exploit the UPR pathway to induce apoptosis in MM cells by overwhelming their protein-folding capacity.
  • Understanding the UPR in MM offers potential therapeutic strategies targeting ER stress for cancer treatment.

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