Abstract
BACH2, a B-cell specific transcription factor, plays a critical role in oxidative stress-mediated apoptosis. Bortezomib (VelcadeTM) is widely used to treat relapsed mantle cell lymphoma (MCL) patients despite varying clinical outcomes. As one of the potential mechanisms of action, bortezomib was reported to elicit endoplasmic reticulum (ER) stress which triggers reactive oxygen species (ROS). In the present study, we investigated the redox-sensitive intracellular mechanism that might play a critical role in bortezomib response in MCL cells. We demonstrated that in MCL cells that are sensitive to bortezomib treatments, BACH2 was translocated to the nucleus in response to bortezomib and induced apoptotic responses through the modulation of anti-oxidative and anti-apoptotic genes. On the other hand, in bortezomib resistant cells, BACH2 expression was confined in the cytoplasm and no suppression of antiapoptotic or antioxidative genes, Nrf2, Gss, CAT, HO-1 and MCL1, was detected. Importantly, levels of BACH2 were significantly higher in bortezomib sensitive MCL patient cells, indicating that BACH2 levels could be an indicator for clinical bortezomib responses. BACH2 translocation to the cytoplasm after phosphorylation was inhibited by PI3K inhibitors and combinatory regimens of bortezomib and PI3K inhibitors sensitized MCL cells to bortezomib. These data suggest that cellular distribution of BACH2 in response to ROS determines the threshold for the induction of apoptosis. Therapies that inhibit BACH2 phosphorylation could be the key for increasing bortezomib cytotoxic response in patients.
Highlights
Mantle Cell Lymphomas (MCL), a rare but deadly sub-type of Non-Hodgkin’s Lymphoma (NHL), are refractory to conventional therapies and display cellular heterogeneity and genomic instability [1,2,3]
Since higher BACH2 expression levels are associated with a better prognosis in large B cell lymphomas, we first examined levels of BACH2 using different MCL cell lines (Jeko, SP53, Mino and Rec-1) using quantitative real time PCR
Recent studies, including our own, showed nuclear factor-kB (NF-kB) activities in some MCL patients and MM patients are resistant to bortezomib treatment [25,36,37,38]
Summary
Mantle Cell Lymphomas (MCL), a rare but deadly sub-type of Non-Hodgkin’s Lymphoma (NHL), are refractory to conventional therapies and display cellular heterogeneity and genomic instability [1,2,3]. The major genetic alteration in MCL that distinguishes them from low-grade B cell lymphomas is the t(11;14)(q13;q32) translocation, leading to increased levels of cyclin D1 (CCND1) gene expression [1,2]. This translocation is a genetic hallmark of most MCL, CCND1 overexpression is not sufficient to induce MCL [4,5], suggesting that other genetic events, possibly acting cooperatively with CCND1 overexpression, are required for the initiation and progression of MCL. Proteasome inhibition prevents the degradation of pro-apoptotic factors, which facilitates the activation of programmed cell death in neoplastic cells [13]; the precise mechanisms of action are controversial
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