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Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue
Hyun Joo Jung1, Zheng Chen, Michael Wang
1Centre for Stem Cell Research, Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Abstract:
Although bortezomib is clinically approved for the treatment of mantle cell lymphoma (MCL), only limited effects of this treatment have been demonstrated. To improve survival for bortezomib-resistant patients, it is necessary to develop new therapeutic strategies. In the present study, we used biochemical and molecular methodologies to demonstrate that tissue transglutaminase (TG) activates downstream NF-κB signaling pathways. The signaling axis from TG to NF-κB could be a new therapeutic target to overcome bortezomib resistance in MCL. TG2 is a calcium-dependent protein cross-linking enzyme reported to be overexpressed in various cancer cells. We found that MCL cells expressed elevated levels of TG2 and that the modification of TG2 activities altered NF-κB expression and downstream signaling in MCL cells. When TG2 signaling was inhibited by calcium blockers, the combination of a calcium blocker (perillyl alcohol) with bortezomib suppressed NF-κB expression and improved the cytotoxicity of bortezomib in MCL cells. Our study is the first to show the expression of TG2 and the contribution of TG2 to NF-κB signaling in MCL. TG2 inhibition may be used as an alternative target anti-MCL therapy, and calcium blockers may be combined with bortezomib to overcome the bortezomib resistance in MCL.
Insights
Tissue transglutaminase (TG) activates NF-κB signaling, contributing to bortezomib resistance in mantle cell lymphoma (MCL). Inhibiting TG2 with calcium blockers alongside bortezomib may improve treatment efficacy for MCL patients.
Area of Science:
- Oncology
- Biochemistry
- Cell Signaling
Background:
- Bortezomib is approved for mantle cell lymphoma (MCL) but shows limited efficacy in some patients.
- Developing strategies to overcome bortezomib resistance is crucial for improving patient survival.
Purpose of the Study:
- To investigate the role of tissue transglutaminase (TG) in activating NF-κB signaling pathways in MCL.
- To explore TG2 as a potential therapeutic target to overcome bortezomib resistance in MCL.
Main Methods:
- Biochemical and molecular methodologies were employed to study TG and NF-κB signaling.
- TG2 activity was modified in MCL cells, and its effects on NF-κB were analyzed.
- The combination of a calcium blocker (perillyl alcohol) with bortezomib was tested for cytotoxicity.
Main Results:
- Tissue transglutaminase (TG) was found to activate downstream NF-κB signaling pathways.
- Mantle cell lymphoma (MCL) cells exhibited elevated levels of TG2.
- Inhibiting TG2 signaling with calcium blockers enhanced bortezomib's cytotoxicity in MCL cells by suppressing NF-κB.
Conclusions:
- This study demonstrates TG2's role in NF-κB signaling and its contribution to bortezomib resistance in MCL.
- TG2 inhibition presents a potential therapeutic strategy for MCL.
- Combining calcium blockers with bortezomib may overcome bortezomib resistance in MCL treatment.
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