Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma (MCL) via manipulation of tissue transglutaminase activities
Menée in vitro, cette étude suggère que, chez des patients atteints d'un lymphome à cellules du manteau, l'ajout d'inhibiteurs calciques au bortezomib pourrait permettre de surmonter la résistance au bortezomib
Although bortezomib is clinically approved for the treatment of Mantle Cell Lymphoma (MCL), only limited effects have been demonstrated. To improve survival for bortezomib-resistant patients it is necessary to develop new therapeutic strategies. In this report, we utilized biochemical and molecular methodologies to demonstrate tissue transglutaminase (TG) activates downstream NF-KB 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 crosslinking enzyme, and was reported to over-expressed in various cancer cells. MCL expressed elevated levels of TG2, and the modification of TG2 activities altered NF-κB expression and downstream signaling in MCL cells. When the TG2 signaling was inhibited via calcium blockers, the combination of a calcium blocker perillyl alcohol (POH) 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 can be an alternative target as anti-MCL therapy, and calcium blockers may be effective combinatory drugs with bortezomib to overcome the bortezomib resistance of MCL.