Downregulation of the unfolded protein response is a potential mechanism for therapeutic resistance in multiple myeloma

2019 ◽  
Vol 19 (10) ◽  
pp. e105
Author(s):  
Scott Goldsmith ◽  
Mark Fiala ◽  
Mark Schroeder ◽  
Tanya Wildes ◽  
Armin Ghobadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Unfolded Protein Response ◽  
Therapeutic Resistance ◽  
Potential Mechanism ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Activation of the Unfolded Protein Response in Acute Leukemia and Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4348-4348
Author(s):  
Toshiaki Yujiri ◽  
Atsuko Tanimura ◽  
Kozo Tagami ◽  
Yukinori Nakamura ◽  
Yukio Tanizawa
Keyword(s):  
Multiple Myeloma ◽  
Acute Leukemia ◽  
Unfolded Protein Response ◽  
Hematological Malignancies ◽  
Hodgkin's Lymphoma ◽  
Myeloma Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Accumulation of unfolded or misfolded proteins within the endoplasmic reticulum triggers the unfolded protein response (UPR). Evidence from several studies suggests that the UPR is activated in various tumors and might play a crucial role in tumor growth. For example, in vitro activation of the UPR alters the sensitivity of tumor cells to chemotherapeutic agents. The role of the UPR in hematological malignancies remains unclear, however. We therefore used real-time RT-PCR to quantitatively assess expression of UPR-related genes in clinical samples [peripheral blood (PB), bone marrow (BM) and lymph node (LN)] from 9 newly diagnosed patients with acute myeloid leukemia (AML), 5 with acute lymphoid leukemia (ALL), 4 with multiple myeloma (MM), 12 with Non-Hodgkin’s lymphoma, 1 with Hodgkin’s lymphoma and 6 with infectious lymphadenopathy. Thirteen healthy controls were also examined. Evaluated was the mRNA expression of a spliced form of X-box DNA-binding protein (XBP1), ER degradation enhancing a-mannosidase-like protein (EDEM), C/EBP-homologous protein (CHOP) and glucose regulated protein 78 (GRP78). We found the transcription levels of all four of these genes to be significantly higher in leukemic blast cells and myeloma cells than in control BM cells or PB mononuclear cells. In particular, leukemic cells from Philadelphia chromosome-positive ALL and aggressive MM cells showed higher levels of UPR-related gene expression. Thus, activation of the UPR might be associated with the malignant characteristics of leukemia and myeloma. By contrast, expression of UPR-related genes was not increased in lymphoma cells compared to LN cells from the patients with infectious lymphadenopathy. The present study provides the first evidence that UPR-related genes are activated in acute leukemia and multiple myeloma cells. Thus, activation of the UPR might play an important role in the development and progression of some hematological malignancies. More comprehensive in vitro studies will be necessary to determine the magnitude of the role played by the UPR, to identify the most important components of the pathway, and to determine which stages of tumor development are regulated by the UPR.

scholarly journals Novel tropolones induce the unfolded protein response pathway and apoptosis in multiple myeloma cells

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 76085-76098 ◽  
Author(s):  
Staci L. Haney ◽  
Cheryl Allen ◽  
Michelle L. Varney ◽  
Kaitlyn M. Dykstra ◽  
Eric R. Falcone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Unfolded Protein Response ◽  
Myeloma Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Tropolone-induced effects on the unfolded protein response pathway and apoptosis in multiple myeloma cells are dependent on iron

2019 ◽  
Vol 77 ◽  
pp. 17-27 ◽  
Author(s):  
Staci L. Haney ◽  
Michelle L. Varney ◽  
Hannah R. Safranek ◽  
Yashpal S. Chhonker ◽  
Narendran G-Dayanandan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Unfolded Protein Response ◽  
Myeloma Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5772-5781 ◽  
Author(s):  
Naoya Mimura ◽  
Mariateresa Fulciniti ◽  
Gullu Gorgun ◽  
Yu-Tzu Tai ◽  
Diana Cirstea ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Inhibition ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

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.

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