Journal
BLOOD
Volume 119, Issue 11, Pages 2568-2578Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-09-377598
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Funding
- National Cancer Institute/National Institutes of Health [P50CA136411]
- CONCERN Foundation
- National Cancer Institute/National Institutes of Health
- American Cancer Society
- [CA16672]
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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-kappa B signaling pathways. The signaling axis from TG to NF-kappa B 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-kappa B 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-kappa B 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-kappa B 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. (Blood. 2012; 119(11):2568-2578)
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