Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells.
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.
Holstein
Sarah A
SA
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
Hohl
Raymond J
RJ
D017209:Apoptosis / Q000187:drug effects; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism*; D007146:Immunoglobulin lambda-Chains / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D054876:Prenylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D000077211:Zoledronic Acid; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism
D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D007147:Immunoglobulin Light Chains; D007146:Immunoglobulin lambda-Chains; D013729:Terpenes; D014415:Tunicamycin; D000077211:Zoledronic Acid; D008148:Lovastatin; D020761:rab1 GTP-Binding Proteins