Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation
Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation
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DOI：
10.1016/j.cellsig.2017.09.020
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发表时间：
2017-12-01
影响因子：
4.8
通讯作者：
Cirone, Mara
中科院分区：
文献类型：
--
作者：
Granato, Marisa;Gilardini Montani, Maria Saveria;Cirone, Mara
二甲双胍是治疗2型糖尿病患者最常用的药物，已被证明具有抗癌特性。在这项研究中，我们发现二甲双胍诱导原发性积液淋巴瘤（PEL）细胞凋亡，这是一种与KSHV相关的侵袭性B细胞淋巴瘤，常规治疗通常无效。二甲双胍的细胞毒性作用与细胞内活性氧的减少、AMPK的激活、mTOR和STAT3等促生存通路的抑制以及v-FLIP的下调相关，v-FLIP是一种潜伏病毒抗原，在PEL细胞存活中也起着关键作用。有趣的是，我们发现二甲双胍可以用来增强硼替佐米介导的对PEL细胞的细胞毒性，并抑制KSHV溶解周期的激活，这是这种治疗的副作用，导致这些细胞的自噬被阻断。机制上，二甲双胍改变硼替佐米激活的UPR，导致BiP表达降低，CHOP上调，Bcl-2下调。总之，这项研究表明，二甲双胍可能代表一个有希望的策略，单独或联合硼替佐米治疗肾衰竭。在后一种情况下，除了发挥更强的细胞毒性作用外，它还可用于抑制硼替佐米诱导的病毒复制，这种病毒复制参与kshv相关恶性肿瘤的维持和进展。
Metformin, the most used drug for the treatment of diabetes type 2 patients, has been shown to have anti-cancer properties. In this study, we found that metformin induced apoptosis in Primary Effusion Lymphoma (PEL) cells, an aggressive B cell lymphoma associated with KSHV against which the conventional therapies usually fail. The cytotoxic effect of metformin correlated with intracellular reactive oxygen species reduction, activation of AMPK, the inhibition of pro-survival pathways such as mTOR and STAT3 and the down-regulation of v-FLIP, a latent viral antigen that also plays a pivotal role in PEL cell survival. Interestingly, we found that metformin could be used to potentiate the bortezomib-mediated cytotoxicity against PEL cells and to inhibit the activation of KSHV lytic cycle, a side effect of this treatment that resulted in a block of autophagy in these cells. Mechanistically, metformin altered UPR activated by bortezomib, leading to a reduced expression of BiP, up regulation of CHOP and down-regulation of Bcl-2. In summary, this study suggests that metformin could represent a promising strategy for the treatment of PEL alone or in combination with bortezomib. In the latter case, besides exerting a stronger cytotoxic effect, it might be used to restrain bortezomib-induced viral replication that is involved in the maintenance and progression of KSHV-associated malignancies.