TY - JOUR
T1 - Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma
AU - Mimura, Naoya
AU - Fulciniti, Mariateresa
AU - Gorgun, Gullu
AU - Tai, Yu Tzu
AU - Cirstea, Diana
AU - Santo, Loredana
AU - Hu, Yiguo
AU - Fabre, Claire
AU - Minami, Jiro
AU - Ohguchi, Hiroto
AU - Kiziltepe, Tanyel
AU - Ikeda, Hiroshi
AU - Kawano, Yutaka
AU - French, Maureen
AU - Blumenthal, Martina
AU - Tam, Victor
AU - Kertesz, Nathalie L.
AU - Malyankar, Uriel M.
AU - Hokenson, Mark
AU - Pham, Tuan
AU - Zeng, Qingping
AU - Patterson, John B.
AU - Richardson, Paul G.
AU - Munshi, Nikhil C.
AU - Anderson, Kenneth C.
PY - 2012/6/14
Y1 - 2012/6/14
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-07-366633
DO - 10.1182/blood-2011-07-366633
M3 - Article
C2 - 22538852
AN - SCOPUS:84862501186
SN - 0006-4971
VL - 119
SP - 5772
EP - 5781
JO - Blood
JF - Blood
IS - 24
ER -