Targeting ubiquitin-activating enzyme induces ER stress-mediated apoptosis in B-cell lymphoma cells

Scott Best, Taylor Hashiguchi, Adam Kittai, Nur Bruss, Cody Paiva, Craig Okada, Tingting Liu, Allison Berger, Alexey Danilov

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Activation of the ER stress response protein kinase R (PKR)-like ER kinase and phosphorylation of eukaryotic translation initiator factor 2α led to upregulation of the proapoptotic molecule C/EBP homologous protein and cell death across a panel of DLBCL cell lines independent of cell of origin. Concurrently, targeting UAE led to accumulation of Cdt1, a replication licensing factor, leading to DNA rereplication, checkpoint activation, and cell cycle arrest. MYC oncoprotein sensitized DLBCL cells to UAE inhibition; engineered expression of MYC enhanced while genetic MYC knockdown protected from TAK-243-induced apoptosis. UAE inhibition demonstrated enhanced ER stress and UPR and increased potency compared with bortezomib in DLBCL cell lines. In vivo treatment with TAK-243 restricted the growth of xenografted DLBCL tumors, accompanied by reduced cell proliferation and apoptosis. Finally, primary patient-derived DLBCL cells, including those expressing aberrant MYC, demonstrated susceptibility to UAE inhibition. In sum, targeting UAE may hold promise as a novel therapeutic approach in NHL.

Original languageEnglish (US)
Pages (from-to)51-62
Number of pages12
JournalBlood advances
Volume3
Issue number1
DOIs
StatePublished - Jan 8 2019

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Ubiquitin-Activating Enzymes
Endoplasmic Reticulum Stress
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
Apoptosis
Proteasome Endopeptidase Complex
Ubiquitin
Heat-Shock Proteins
Unfolded Protein Response
Non-Hodgkin's Lymphoma
Transcription Factor CHOP
Cell Line
Proteasome Inhibitors
Ubiquitination
Oncogene Proteins
Licensure
Cell Cycle Checkpoints
Endoplasmic Reticulum
Protein Kinases
Cell Death

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Targeting ubiquitin-activating enzyme induces ER stress-mediated apoptosis in B-cell lymphoma cells. / Best, Scott; Hashiguchi, Taylor; Kittai, Adam; Bruss, Nur; Paiva, Cody; Okada, Craig; Liu, Tingting; Berger, Allison; Danilov, Alexey.

In: Blood advances, Vol. 3, No. 1, 08.01.2019, p. 51-62.

Research output: Contribution to journalArticle

Best, Scott ; Hashiguchi, Taylor ; Kittai, Adam ; Bruss, Nur ; Paiva, Cody ; Okada, Craig ; Liu, Tingting ; Berger, Allison ; Danilov, Alexey. / Targeting ubiquitin-activating enzyme induces ER stress-mediated apoptosis in B-cell lymphoma cells. In: Blood advances. 2019 ; Vol. 3, No. 1. pp. 51-62.
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