Abstract
Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive non-Hodgkin lymphomas. It is curable but one-third of cases are refractory to therapy or relapse after initial response highlighting the urgent need for developing novel therapeutic approaches. Targeting sirtuins, particularly SIRT1 by genetic approaches or using pharmaceutical inhibitor tenovin-6, has shown promising therapeutic potential in various hematopoietic malignancies. However, it remains unknown whether these approaches are effective for DLBCL. In this study, we have found that tenovin-6 potently inhibits the proliferation and survival of DLBCL cells. Surprisingly, specific knockdown of SIRT1/2/3 has no effect on DLBCL. Mechanistically, tenovin-6 increases the level of microtubule-associated protein 1 light chain 3B (LC3B)-II in a SIRT1/2/3- and p53-independent manner in DLBCL cell lines. Tenovin-6-mediated increase of LC3B-II is through inhibition of classical autophagy pathway. Furthermore, inhibition of the autophagy pathway by using other inhibitors or by knocking down key genes in the pathway impairs cell proliferation and survival of DLBCL cells. These results indicate that targeting the autophagic pathway could be a novel therapeutic strategy for DLBCL and that precaution should be taken to interpret data where tenovin-6 was used as an inhibitor of sirtuins.
Highlights
Diffuse large B cell lymphoma (DLBCL), the most common B cell tumor in adults, displays marked clinical heterogeneity
Inhibition of the autophagy pathway by using other inhibitors or by knocking down key genes in the pathway impairs cell proliferation and survival of Diffuse large B-cell lymphoma (DLBCL) cells. These results indicate that targeting the autophagic pathway could be a novel therapeutic strategy for DLBCL and that precaution should be taken to interpret data where tenovin-6 was used as an inhibitor of sirtuins
Tenovin-6 induced apoptosis in a dose- and time-dependent manner in all 6 cell lines (Figure 1D and 1E). These results indicated that tenovin-6 potently inhibited cell proliferation and survival of DLBCL cells
Summary
Diffuse large B cell lymphoma (DLBCL), the most common B cell tumor in adults, displays marked clinical heterogeneity. An emerging consensus in the field is that a better understanding of DLBCL biology may be the most effective way to improve the survival rate of patients who are refractory or have a relapse [2]. There has been steady progress in elucidating the pathogenesis of DLBCL. Gene expression profiling analyses have defined DLBCL signatures that are associated with a putative cell-of-origin DLBCL) or mechanisms of transformation (consensus cluster classification, CCC) [3, 4], observations that have already guided rational clinical initiatives. Massively parallel sequencing uncovered previous unsuspecting genetic lesions in DLBCL [5], suggesting that important elements of DLBCL biology remain to be elucidated creating novel opportunities for tailored therapeutic interventions
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