Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation

M. Granato, M. S. Gilardini Montani, M. A. Romeo, R. Santarelli, R. Gonnella, G. D'Orazi, A. Faggioni, M. Cirone

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)239-247
Number of pages9
JournalCellular Signalling
Volume40
DOIs
Publication statusPublished - Dec 1 2017

Fingerprint

Primary Effusion Lymphoma
Unfolded Protein Response
Human Herpesvirus 8
Metformin
Apoptosis
Down-Regulation
AMP-Activated Protein Kinases
Viral Antigens
Autophagy
B-Cell Lymphoma
Therapeutics
Type 2 Diabetes Mellitus
Bortezomib
Reactive Oxygen Species
Neoplasms
Cell Survival
Up-Regulation
Maintenance
Survival
Pharmaceutical Preparations

Keywords

  • Autophagy
  • Bortezomib
  • ER-stress
  • KSHV
  • Metformin
  • PEL

Cite this

Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation. / Granato, M.; Montani, M. S. Gilardini; Romeo, M. A.; Santarelli, R.; Gonnella, R.; D'Orazi, G.; Faggioni, A.; Cirone, M.

In: Cellular Signalling, Vol. 40, 01.12.2017, p. 239-247.

Research output: Contribution to journalArticle

Granato, M. ; Montani, M. S. Gilardini ; Romeo, M. A. ; Santarelli, R. ; Gonnella, R. ; D'Orazi, G. ; Faggioni, A. ; Cirone, M. / Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation. In: Cellular Signalling. 2017 ; Vol. 40. pp. 239-247.
@article{64940d2f5dc64f6e8785cbafc0cce3b9,
title = "Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation",
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 = "Autophagy, Bortezomib, ER-stress, KSHV, Metformin, PEL",
author = "M. Granato and Montani, {M. S. Gilardini} and Romeo, {M. A.} and R. Santarelli and R. Gonnella and G. D'Orazi and A. Faggioni and M. Cirone",
note = "LR: 20171022; CI: Copyright (c) 2017; JID: 8904683; OTO: NOTNLM; 2017/08/10 00:00 [received]; 2017/09/26 00:00 [revised]; 2017/09/26 00:00 [accepted]; 2017/10/02 06:00 [pubmed]; 2017/10/02 06:00 [medline]; 2017/10/02 06:00 [entrez]; ppublish",
year = "2017",
month = "12",
day = "1",
doi = "S0898-6568(17)30256-5 [pii]",
language = "English",
volume = "40",
pages = "239--247",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation

AU - Granato, M.

AU - Montani, M. S. Gilardini

AU - Romeo, M. A.

AU - Santarelli, R.

AU - Gonnella, R.

AU - D'Orazi, G.

AU - Faggioni, A.

AU - Cirone, M.

N1 - LR: 20171022; CI: Copyright (c) 2017; JID: 8904683; OTO: NOTNLM; 2017/08/10 00:00 [received]; 2017/09/26 00:00 [revised]; 2017/09/26 00:00 [accepted]; 2017/10/02 06:00 [pubmed]; 2017/10/02 06:00 [medline]; 2017/10/02 06:00 [entrez]; ppublish

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - Bortezomib

KW - ER-stress

KW - KSHV

KW - Metformin

KW - PEL

U2 - S0898-6568(17)30256-5 [pii]

DO - S0898-6568(17)30256-5 [pii]

M3 - Article

VL - 40

SP - 239

EP - 247

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

ER -