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

Area of Science:

• Molecular Biology
• Oncology
• Drug Development

Background:

• The ubiquitin proteasome system (UPS) is crucial for cellular stress management in cancer.
• Existing proteasome inhibitors show limited efficacy in non-Hodgkin lymphoma (NHL).
• Novel strategies targeting the UPS are needed for NHL treatment.

Purpose of the Study:

• To investigate the efficacy of TAK-243, a ubiquitin activating enzyme (UAE) inhibitor, in diffuse large B-cell lymphoma (DLBCL).
• To elucidate the mechanisms of action of UAE inhibition in DLBCL cells.
• To evaluate TAK-243 as a potential therapeutic agent for NHL.

Main Methods:

• Treatment of DLBCL cell lines with TAK-243, a small-molecule UAE inhibitor.
• Assessment of ubiquitin signaling, protein ubiquitination, ER stress, and UPR.
• Analysis of Cdt1 accumulation, DNA rereplication, cell cycle arrest, and apoptosis.
• Evaluation of MYC oncoprotein's role in DLBCL sensitivity to TAK-243.
• In vivo studies using xenografted DLBCL tumors and analysis of patient-derived DLBCL cells.

Main Results:

• TAK-243 disrupted ubiquitin signaling and protein ubiquitination, inducing ER stress and UPR in DLBCL cells.
• UAE inhibition led to Cdt1 accumulation, DNA rereplication, cell cycle arrest, and apoptosis, independent of DLBCL cell of origin.
• MYC oncoprotein sensitized DLBCL cells to TAK-243; MYC knockdown conferred protection.
• TAK-243 demonstrated enhanced ER stress and UPR compared to bortezomib and inhibited xenograft tumor growth.
• Patient-derived DLBCL cells, including those with aberrant MYC, were susceptible to TAK-243.

Conclusions:

• Targeting UAE with TAK-243 is a promising therapeutic strategy for DLBCL and potentially other NHL subtypes.
• TAK-243 induces cell death through ER stress, UPR, and DNA rereplication.
• The findings support further clinical development of UAE inhibitors for NHL treatment.