Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells

Leuk Res. 2011 Apr;35(4):551-9. doi: 10.1016/j.leukres.2010.08.008. Epub 2010 Sep 9.

Abstract

Myeloma is characterized by the overproduction and secretion of monoclonal protein. Inhibitors of the isoprenoid biosynthetic pathway (IBP) have pleiotropic effects in myeloma cells. To investigate whether IBP inhibition interferes with monoclonal protein secretion, human myeloma cells were treated with specific inhibitors of the IBP or prenyltransferases. These studies demonstrate that agents that inhibit Rab geranylgeranylation disrupt light chain trafficking, lead to accumulation of light chain in the endoplasmic reticulum, activate the unfolded protein response pathway and induce apoptosis. These studies provide a novel mechanism of action for IBP inhibitors and suggest that further exploration of Rab-targeted agents in myeloma is warranted.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects
  • Biosynthetic Pathways / drug effects
  • Biosynthetic Pathways / physiology
  • Cell Line, Tumor
  • Diphosphonates / pharmacology
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Imidazoles / pharmacology
  • Immunoblotting
  • Immunoglobulin Light Chains / genetics
  • Immunoglobulin Light Chains / metabolism*
  • Immunoglobulin lambda-Chains / blood
  • Immunoglobulin lambda-Chains / genetics
  • Immunoglobulin lambda-Chains / metabolism
  • Lovastatin / pharmacology
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • Prenylation / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Terpenes / metabolism*
  • Tunicamycin / pharmacology
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / physiology*
  • Zoledronic Acid
  • rab1 GTP-Binding Proteins / metabolism

Substances

  • Diphosphonates
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Imidazoles
  • Immunoglobulin Light Chains
  • Immunoglobulin lambda-Chains
  • Terpenes
  • Tunicamycin
  • Zoledronic Acid
  • Lovastatin
  • rab1 GTP-Binding Proteins