Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities

Abstract

IntroductionMantle cell lymphoma (MCL) is an aggressive subtype of B-cell lymphoma that accounts for 5%-7% of cases of non-Hodgkin lymphoma. Despite good responses with first-line treatments for newly diagnosed, untreated MCL patients, 1-3 MCL patients often relapse and demonstrate highly refractory responses to common antilymphoma chemotherapy, which results in inevitable chemoresistance and poor clinical outcomes. [4][5][6][7] Bortezomib (Velcade), a reversible inhibitor of the 26S proteasome, first gained United States Food and Drug Administration approval as a single-agent treatment in patients with relapsed or refractory MCL. 8 Bortezomib inhibits the ubiquitin-proteasome pathway and alters multiple cellular signaling cascades, including those regulating cell growth, differentiation, and survival. [9][10][11] For example, proteasome inhibition prevents the degradation of proapoptotic factors, which facilitates the activation of programmed cell death in neoplastic cells; however, the precise mechanisms of action are controversial.One of the known bortezomib targets for inhibition is NF-B and its related pathway. Constitutive NF-B expression has been reported in MCL cell lines and primary cells. 12 However, therapies such as bortezomib targeting NF-B have shown limited effects in MCL. [13][14][15] Bortezomib was also reported to elicit the unfolded protein response, which is activated when the physiologic environment of the endoplasmic reticulum is altered. [16][17][18] The induction of endoplasmic reticulum stress induces reactive oxygen species, which affects treatment responses to bortezomib in MCL 18 and multiple myeloma. 19 In addition, some studies have suggested that bortezomib could increase NF-B activity 20,21 or the presence of bortezomib-resistant NF-B activity in MCL. 13 The resistance to drugs such as bortezomib in MCL suggest the presence of drug-resistant populations in MCL. In a previous study, we prospectively identified stem-like cells in MCL, which we have termed MCL-initiating cells (MCL-ICs). 22 The stem-like MCL cells (CD45 ϩ CD19 Ϫ CD34 Ϫ CD3 Ϫ ) were highly tumorigenic and display self-renewal capacities in NOD/SCID mice. In contrast, the majority of the tumor population contains CD45 ϩ CD19 ϩ MCL cells, which show no self-renewal capacity and have greatly reduced tumorigenicity. 22 We also demonstrated that these CD45 ϩ CD19 Ϫ MCL-ICs confer drug resistance properties to MCL. MCL-ICs were highly resistant in vitro to clinically relevant anti-MCL chemotherapeutic regimens compared with bulk CD45 ϩ CD19 ϩ MCL cells. 23 Moreover, CD45 ϩ CD19 Ϫ MCL-ICs were resistant to bortezomib and bortezomib-based chemotherapeutic regimens despite constitutive NF-B expression. 24 Bortezomibbased regimens targeted CD45 ϩ CD19 Ϫ MCL-ICs less efficiently compared with CD45 ϩ CD19 ϩ bulk MCL cells. Based on these findings, a new strategy is required to overcome bortezomib resistance in MCL.Recent studies have demonstrated that perillyl alcohol (POH), a naturally occurring monoterpene that inhibits L-type ...

4-hexylresorcinol exerts antitumor effects via suppression of calcium oscillation and its antitumor effects are inhibited by calcium channel blockers

“…The calcium is important in the epithelial cell differentiation (22). 4-HR inhibits TG-2 activity (14) and the activity of TG-2 is also calcium dependent (23). Therefore, the molecular mechanisms of the observed 4-HR-mediated effects may be partly dependent on calcium.…”

Transglutaminases: recent achievements and new sources

“…Transglutaminases (TGases), also named protein-glutamine γ-glutamyltransferases, are enzymes belonging to the proteases class that catalyze post-translational modifications in many proteins by inter-or intramolecular cross-linking through acyl-transfer between y-carboxyamide groups of glutamine residues and ε-amino groups of lysines, or other primary amine, resulting in the formation of γ-glutamyl-ε-lysine peptide chain bridges Campos et al 2010;Hu et al 2011;Jung et al 2012;Li et al 2013;Lorand and Graham 2003). In the latter case, it is able to modify the protein substrate by "cationization" or by forming inter-or intramolecular bridges through polyamines of different length ).…”

TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

“…The DNA-binding activities of NF-kB components, TG2 enzymatic activity and IL-6 levels were determined by ELISA assays, as previously described (11,26). …”

“…It has multiple physiologic functions and is associated with cancer cell survival, metastatic behavior and drug resistance (5–9). TG2 has been proposed as a promising therapeutic target in the treatment of human cancers (10,11). Increasing evidence has demonstrated that TG2 is closely associated with constitutive nuclear factor-kappa B (NF-kB) expression in cancer cells (12,13).…”

“…Increasing evidence has demonstrated that TG2 is closely associated with constitutive nuclear factor-kappa B (NF-kB) expression in cancer cells (12,13). Our previous study has shown that TG2 forms complexes with NF-kB components, which drives the translocation of NF-kB to the nucleus and constitutive expression of NF-kB (11). Moreover, TG2 and NF-kB are highly expressed in MCL cells that are stem-like, suggesting that TG2/NF-kB signaling plays a critical role in MCL progression (11).…”