Abstract
BackgroundBortezomib (BTZ) is an inhibitor of the proteasome that has been used to treat patients with mantle cell lymphoma (MCL), but the resistance to BTZ in clinical cases remains a major drawback. BACH2 is a lymphoid-specific transcription repressor recognized as a tumor suppressor in MCL. Reduced BACH2 levels contribute to BTZ resistance; however, the molecular events underlying BACH2-mediated BTZ resistance are largely unclear.MethodsWe silenced BACH2 in MCL cells using a lentiviral shRNA-mediated knockdown system. Bioinformatic, real-time RT-PCR, immunoblotting and a series of functional assays were performed to describe the molecular mechanisms underlying BTZ resistance in MCL. The therapeutic effects of chemicals were evaluated on numerous cellular and molecular processes in resistant MCL cell lines and xenografts.ResultsIn resistant cells, BTZ-triggered mild oxidative stress induced a strong activation of PI3K-AKT signaling, which further blocked nuclear translocation of BACH2. Defective nuclear translocation of BACH2 or silencing BACH2 removed its transcriptional repression on HMOX1, leading to upregulation of heme oxygenase-1 (HO-1). Increased HO-1 further maintained reactive oxygen species (ROS) within a minimal tumor-promoting level and enhanced cytoprotective autophagy. Interestingly, although mild increase in ROS exhibited a pro-tumorigenic effect on resistant cells, simply blocking ROS by antioxidants did not lead to cell death but aggravated BTZ resistance via stabilizing BACH1, the other member of BACH family. Instead, 3-methyladenine (3-MA), a dual inhibitor to suppress PI3K signaling and autophagosome formation, sensitized resistant MCL cells to BTZ, both in vitro and in vivo.ConclusionOur results dissected the interconnected molecular network in resistant MCL cells in which 3-MA represents an effective therapeutic strategy to overcome BTZ resistance. Notably, BACH1 and BACH2, albeit from the same family, are likely to play opposite roles in pathogenesis and progression of MCL.
Highlights
Bortezomib (BTZ) is an inhibitor of the proteasome that has been used to treat patients with mantle cell lymphoma (MCL), but the resistance to BTZ in clinical cases remains a major drawback
Further study identified that the subcellular localization of BTB and CNC homology 2 (BACH2), a lymphoid-specific transcription repressor recognized as a tumor suppressor in MCL [13], determines oxidative stress responses to BTZ in MCL
We found that a minimal increase of reactive oxygen species (ROS) in BTZ-resistant MCL cells greatly activated PI3K-AKT pathway, which further caused defective nuclear translocation of BACH2, removing its transcriptional repression on heme oxygenase-1 (HMOX1)
Summary
Bortezomib (BTZ) is an inhibitor of the proteasome that has been used to treat patients with mantle cell lymphoma (MCL), but the resistance to BTZ in clinical cases remains a major drawback. BTZ-induced ROS triggers cytoprotective autophagy in resistant cells [15], and silencing BACH2 contributes to BTZ resistance [13]. None of these studies delineate what causes defective nuclear translocation of BACH2 in BTZresistant MCL cells, and which pathways are involved in BTZ resistance upon BACH2 silencing. It remains ill-defined what molecular events determine BTZ-induced cytotoxicity, and more importantly, can we find a better way to overcome BTZ resistance in MCL? It remains ill-defined what molecular events determine BTZ-induced cytotoxicity, and more importantly, can we find a better way to overcome BTZ resistance in MCL? we sought to integrate multiple lines of evidence together and find the crosslink between each other
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