Oxidant species are involved in T/B-mediated ERK1/2 phosphorylation that activates p53-p21 axis to promote KSHV lytic cycle in PEL cells

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

Research output: Contribution to journalArticle

Abstract

KSHV is a gammaherpesvirus strongly associated to human cancers such as Primary Effusion Lymphoma (PEL) and Kaposi's Sarcoma. The naturally virus-infected tumor cells usually display latent infection since a minority of cells undergoes spontaneous viral replication. The lytic cycle can be induced in vitro upon appropriate stimuli such as TPA (T), alone or in combination with butyrate (B), (T/B). In previous studies, Protein Kinase C (PKC) delta, Extracellular Signal-regulated Kinase1/2 (ERK1/2) and p53-p21 axis have been separately reported to play a role in KSHV reactivation from latency. Here, we found that these pathways were interconnected to induce KSHV lytic cycle in PEL cells treated with T/B. T/B also increased H2O2 that played an important role in the activation of these pathways. Oxidant specie production correlated with PKC delta activation, as the PKC delta inhibitor rottlerin reduced both H2O2 and KSHV lytic antigen expression. H2O2 contributed to T/B-mediated ERK1/2 activation that mediated p53 phosphorylation at serine 15 (Ser15) and increased p21 expression. Oxidant specie inhibition by quercetin indeed strongly reduced the activation of these pathways, lytic antigen expression and interestingly it also increased T/B-induced cell death. The use of ERK inhibitor PD98059 or p53 silencing demonstrated the importance of p53Ser15 phosphorylation and of p53-p21 axis in KSHV lytic cycle activation. Understanding the role of oxidant species and the molecular mechanisms involved in KSHV lytic cycle induction is particularly important since oxidant species represent the most physiological stimulus for viral reactivation in vivo and it is known that viral production contributes to the maintenance/progression of KSHV associated malignancies.
Original languageEnglish
Pages (from-to)327-335
Number of pages9
JournalFree Radical Biology and Medicine
Volume112
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Primary Effusion Lymphoma
Human Herpesvirus 8
Phosphorylation
Oxidants
Protein Kinase C-delta
Chemical activation
Antigens
Butyrates
Quercetin
Cell death
Viruses
Serine
Oncogenic Viruses
Tumors
Kaposi's Sarcoma
Cells
Neoplasms
Cell Death
Maintenance

Keywords

  • ERK1/2
  • KSHV
  • Lytic cycle
  • Oxidant species
  • P21
  • P53
  • PEL
  • PKC delta
  • ROS
  • TPA/Butyrate

Cite this

Oxidant species are involved in T/B-mediated ERK1/2 phosphorylation that activates p53-p21 axis to promote KSHV lytic cycle in PEL cells. / Gonnella, R.; Yadav, S.; Montani, M. S. Gilardini; Granato, M.; Santarelli, R.; Garufi, A.; D'Orazi, G.; Faggioni, A.; Cirone, M.

In: Free Radical Biology and Medicine, Vol. 112, 01.11.2017, p. 327-335.

Research output: Contribution to journalArticle

Gonnella, R. ; Yadav, S. ; Montani, M. S. Gilardini ; Granato, M. ; Santarelli, R. ; Garufi, A. ; D'Orazi, G. ; Faggioni, A. ; Cirone, M. / Oxidant species are involved in T/B-mediated ERK1/2 phosphorylation that activates p53-p21 axis to promote KSHV lytic cycle in PEL cells. In: Free Radical Biology and Medicine. 2017 ; Vol. 112. pp. 327-335.
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AU - Yadav, S.

AU - Montani, M. S. Gilardini

AU - Granato, M.

AU - Santarelli, R.

AU - Garufi, A.

AU - D'Orazi, G.

AU - Faggioni, A.

AU - Cirone, M.

N1 - LR: 20170930; CI: Copyright (c) 2017; JID: 8709159; OTO: NOTNLM; 2017/03/28 00:00 [received]; 2017/07/31 00:00 [revised]; 2017/08/05 00:00 [accepted]; 2017/08/13 06:00 [pubmed]; 2017/08/13 06:00 [medline]; 2017/08/13 06:00 [entrez]; ppublish

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N2 - KSHV is a gammaherpesvirus strongly associated to human cancers such as Primary Effusion Lymphoma (PEL) and Kaposi's Sarcoma. The naturally virus-infected tumor cells usually display latent infection since a minority of cells undergoes spontaneous viral replication. The lytic cycle can be induced in vitro upon appropriate stimuli such as TPA (T), alone or in combination with butyrate (B), (T/B). In previous studies, Protein Kinase C (PKC) delta, Extracellular Signal-regulated Kinase1/2 (ERK1/2) and p53-p21 axis have been separately reported to play a role in KSHV reactivation from latency. Here, we found that these pathways were interconnected to induce KSHV lytic cycle in PEL cells treated with T/B. T/B also increased H2O2 that played an important role in the activation of these pathways. Oxidant specie production correlated with PKC delta activation, as the PKC delta inhibitor rottlerin reduced both H2O2 and KSHV lytic antigen expression. H2O2 contributed to T/B-mediated ERK1/2 activation that mediated p53 phosphorylation at serine 15 (Ser15) and increased p21 expression. Oxidant specie inhibition by quercetin indeed strongly reduced the activation of these pathways, lytic antigen expression and interestingly it also increased T/B-induced cell death. The use of ERK inhibitor PD98059 or p53 silencing demonstrated the importance of p53Ser15 phosphorylation and of p53-p21 axis in KSHV lytic cycle activation. Understanding the role of oxidant species and the molecular mechanisms involved in KSHV lytic cycle induction is particularly important since oxidant species represent the most physiological stimulus for viral reactivation in vivo and it is known that viral production contributes to the maintenance/progression of KSHV associated malignancies.

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KW - KSHV

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KW - Oxidant species

KW - P21

KW - P53

KW - PEL

KW - PKC delta

KW - ROS

KW - TPA/Butyrate

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JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

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