Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma

Vincenz, Lisa; Jäger, Richard; O’Dwyer, Michael; Samali, Afshin

doi:10.1158/1535-7163.mct-12-0782

Cited by 142 publications

(143 citation statements)

References 74 publications

(97 reference statements)

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“…The IRE1α/XBP1 pathway is often activated in cancers and has recently emerged as a potential molecular target for anticancer therapy (1,5,(39)(40)(41)(42)(43), especially for multiple myeloma, which is characterized by malignant plasma cells producing a high amount of immunoglobulin (26,42,44,45). These previous studies showed that the pharmacological inhibition of IRE1α endonuclease significantly suppressed myeloma tumor growth in a model of human malignant myeloma xenografts, corroborating the idea that the IRE1α/XBP1 pathway may serve as a promising molecular target.…”

Section: Discussionmentioning

confidence: 99%

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda¹,

Yoda²,

Iwawaki³

et al. 2015

J. Clin. Invest.

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(T. Tohmonda).lowed by Alexa Fluor 488-conjugated anti-rabbit IgG (Invitrogen); nuclei were counterstained with DAPI. Images of the cells were acquired with Olympus DP controller software via an Olympus DP70 camera mounted on an Olympus IX71 microscope at room temperature. The objective was a ×100 APO/1.65 NA lens. Images were processed with Adobe Photoshop CS6 for contrast correction and to generate merged images.Statistics. All statistical analyses were performed using Prism 6 (GraphPad Software). Two-tailed Student's t tests for 2 samples assuming equal variances were used to calculate the P values. P < 0.05 was considered significant.Study approval. All of the animal experiments in this study were approved by the Institutional Animal Care and Use Committee of the

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Section: Discussionmentioning

confidence: 99%

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda¹,

Yoda²,

Iwawaki³

et al. 2015

J. Clin. Invest.

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“…Comparisons were made to multiple myeloma, known to be associated with UPR activation. 39 Overall, PERK and XBP1 were widely detected in LN samples; 11 of 11 and 10 of 11 samples were positive for PERK and XBP1 expression, respectively. Similar to myeloma samples, PERK immunostaining was largely extranuclear, consistent with endoplasmic reticulum localization.…”

mentioning

confidence: 83%

Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK

Krysov

Steele

Coelho

et al. 2014

Blood

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Key Points• Stimulation of the B-cell receptor of chronic lymphocytic leukemia cells results in activation of an unfolded protein response.• Unfolded protein response activation following surface immunoglobulin M stimulation in vitro is dependent on the activity of BTK and SYK.B-cell receptor (BCR) signaling plays a key role in the behavior of chronic lymphocytic leukemia (CLL). However, cellular consequences of signaling are incompletely defined.Here we explored possible links between BCR signaling and the unfolded protein response (UPR), a stress response pathway that can promote survival of normal and malignant cells. Compared with normal B cells, circulating CLL cells expressed increased, but variable, levels of UPR components. Higher expression of CHOP and XBP1 RNAs was associated with more aggressive disease. UPR activation appeared due to prior tissuebased antigenic stimulation because elevated expression of UPR components was detected within lymph node proliferation centers. Basal UPR activation also correlated closely with surface immunoglobulin M (sIgM) signaling capacity in vitro in both IGHV unmutated CLL and within mutated CLL. sIgM signaling increased UPR activation in vitro with responders showing increased expression of CHOP and XBP1 RNAs, and PERK and BIP proteins, but not XBP1 splicing. Inhibitors of BCR-associated kinases effectively prevented sIgM-induced UPR activation. Overall, this study demonstrates that sIgM signaling results in activation of some components the UPR in CLL cells. Modulation of the UPR may contribute to variable clinical behavior, and its inhibition may contribute to clinical responses to BCR-associated kinase inhibitors. (Blood. 2014;124(20):3101-3109) IntroductionChronic lymphocytic leukemia (CLL) provides a unique opportunity to understand how antigen can influence the behavior of malignant lymphocytes. It also acts as a model for the development of novel therapies targeted toward B-cell receptor (BCR) signaling pathways. [1][2][3][4] CLL comprises 2 major subsets with differing levels of somatic hypermutation of tumor IGV genes. CLL with unmutated IGV (U-CLL) derives from naïve CD5 1 CD27 2 B cells of the normal natural antibody repertoire, whereas CLL with mutated IGV genes (M-CLL) may derive from postgerminal center CD5 1 CD27 1 cells. 5,6 Importantly, these subsets have distinct clinical behavior, and U-CLL has a more aggressive clinical course. Antigen signaling is thought to be ongoing in both subsets and, rather than the presence or absence of signaling, it is the balance between distinct types of responses that appears to determine clinical behavior. 1 Anergy, a state of cellular lethargy that is induced following antigen engagement in the absence of T-cell help, 7 is observed in all CLL but is particularly prominent in M-CLL.1 By contrast, positive antigen signaling leading to proliferation and survival appears more evident in U-CLL. The importance of antigen signaling for CLL is emphasized by recent results that have demonstrated the clinical effectivenes...

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“…Defense against stress misfolded proteins exert on the endoplasmic reticulum (ER) has been identified as Achilles heel of multiple myeloma (3). Proteins destined for secretion enter the ER in an incompletely folded state and factors commonly found in cancer, like augmented protein synthesis, nutrient deficiency, and hypoxia increase them or impair their folding exerting ER stress (4).…”

Section: Introductionmentioning

confidence: 99%

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

et al. 2016

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Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrowsparing compound, exhibited a submicromolar IC 50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in activesite CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma.

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Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma

Cited by 142 publications

References 74 publications

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

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