Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy.
Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy.
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DOI：
10.18632/oncotarget.14741
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发表时间：
2017-02-28
期刊：
影响因子：
--
通讯作者：
Gao SJ
中科院分区：
文献类型：
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作者：
Yuan H;He M;Cheng F;Bai R;da Silva SR;Aguiar RC;Gao SJ
弥漫性大b细胞淋巴瘤（DLBCL）是侵袭性最强的非霍奇金淋巴瘤之一。它是可治愈的，但三分之一的病例难以治疗或在初步反应后复发，这突出表明迫切需要开发新的治疗方法。靶向sirtuins，特别是通过遗传方法或使用药物抑制剂tenovin-6靶向SIRT1，在各种造血恶性肿瘤中显示出良好的治疗潜力。然而，这些方法对DLBCL是否有效尚不清楚。在本研究中，我们发现tenovin-6能有效抑制DLBCL细胞的增殖和存活。令人惊讶的是，特异性敲低SIRT1/2/3对DLBCL没有影响。在机制上，tenovin-6以SIRT1/2/3-和p53独立的方式增加DLBCL细胞系中微管相关蛋白1轻链3B (LC3B)- ii的水平。tenovin -6通过抑制经典自噬途径介导LC3B-II的升高。此外，通过使用其他抑制剂或敲除自噬途径中的关键基因来抑制自噬途径会损害DLBCL细胞的细胞增殖和存活。这些结果表明，靶向自噬途径可能是DLBCL的一种新的治疗策略，应该采取预防措施来解释使用tenovin-6作为sirtuins抑制剂的数据。
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.