Abstract
Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1α endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential therapeutic option in MM.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Combined Chemotherapy Protocols / pharmacology
-
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
-
Benzoquinones / pharmacology
-
Bone Marrow Cells / cytology
-
Bone Marrow Cells / drug effects
-
Bone Marrow Cells / metabolism
-
Boronic Acids / pharmacology
-
Boronic Acids / therapeutic use
-
Bortezomib
-
Cell Death / drug effects
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
DNA-Binding Proteins / genetics*
-
Endoplasmic Reticulum Stress / drug effects
-
Endoribonucleases / antagonists & inhibitors*
-
Endoribonucleases / metabolism
-
Enzyme Activation / drug effects
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology
-
Enzyme Inhibitors / therapeutic use
-
Humans
-
Interleukin-6 / pharmacology
-
Lactams, Macrocyclic / pharmacology
-
Mice
-
Multiple Myeloma / drug therapy*
-
Multiple Myeloma / genetics
-
Multiple Myeloma / pathology
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / metabolism
-
Pyrazines / pharmacology
-
Pyrazines / therapeutic use
-
RNA Splicing / drug effects*
-
RNA Splicing / genetics
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Regulatory Factor X Transcription Factors
-
Signal Transduction / drug effects
-
Stromal Cells / cytology
-
Stromal Cells / drug effects
-
Stromal Cells / metabolism
-
Transcription Factors / genetics*
-
Unfolded Protein Response / drug effects
-
X-Box Binding Protein 1
-
eIF-2 Kinase / metabolism
Substances
-
Benzoquinones
-
Boronic Acids
-
DNA-Binding Proteins
-
Enzyme Inhibitors
-
Interleukin-6
-
Lactams, Macrocyclic
-
Pyrazines
-
RNA, Messenger
-
Regulatory Factor X Transcription Factors
-
Transcription Factors
-
X-Box Binding Protein 1
-
XBP1 protein, human
-
Xbp1 protein, mouse
-
tanespimycin
-
Bortezomib
-
ERN1 protein, human
-
PERK kinase
-
Protein Serine-Threonine Kinases
-
eIF-2 Kinase
-
Endoribonucleases