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

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.

• Authors: Scott Best, Taylor Hashiguchi, Adam Kittai, Nur Bruss, Cody Paiva, Craig Okada, Tingting Liu, Allison Berger, Alexey V Danilov
• Journal: Blood advances (Blood Adv) Vol. 3 Issue 1 Pg. 51-62 (01 08 2019) ISSN: 2473-9537 [Electronic] United States
• PMID: 30617217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• Proteasome Inhibitors
• Ubiquitin-Activating Enzymes

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• DNA Damage
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Endoplasmic Reticulum Stress (drug effects)
• Genes, myc
• Humans
• Lymphoma, B-Cell (drug therapy, metabolism, pathology)
• Lymphoma, Large B-Cell, Diffuse (drug therapy, metabolism, pathology)
• Mice
• Proteasome Inhibitors (pharmacology)
• Ubiquitin-Activating Enzymes (antagonists & inhibitors, metabolism)
• Unfolded Protein Response
• Xenograft Model Antitumor Assays