Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5509274 | Cellular Signalling | 2017 | 9 Pages |
Abstract
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.
Keywords
AMPKLC3IRE1UPRATF64E-BP1KSHVLANABAFmTORATF4STAT3AMP-activated protein kinaseC/EBP-homologous proteinER-stressROSinositol-requiring enzyme 1AutophagyPELER stressEndoplasmic reticulum stressbafilomycin A1BortezomibCHOPactivating transcription factor 4activating transcription factor 6Primary effusion lymphomasignal transducer and activator of transcription 3MetforminMETmammalian target of rapamycinKaposi's sarcoma-associated herpesvirusUnfolded protein responsemicrotubule-associated protein 1A/1B-light chain 3Reactive oxygen species
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Authors
Marisa Granato, Maria Saveria Gilardini Montani, Maria Anele Romeo, Roberta Santarelli, Roberta Gonnella, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone,