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IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling

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2019
949.pdf (3.766Mb)
Authors
Subotički, Tijana
Mitrović-Ajtić, Olivera
Beleslin-Čokić, Bojana
Bjelica, Sunčica
Đikić, Dragoslava
Diklić, Miloš
Leković, Danijela
Gotić, Mirjana
Santibanez, Juan
Noguchi, Constance T.
Čokić, Vladan
Article (Published version)
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Abstract
Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of ...PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.

Keywords:
cell cycle / ERK1/2 signaling / inflammation / JAK1/2 inhibition / myeloproliferative neoplasm
Source:
Cell Biology International, 2019, 43, 2, 192-206
Publisher:
  • Wiley, Hoboken
Funding / projects:
  • The pathogenetic mechanism in hematological malignancies (RS-175053)
  • Swiss National Science Foundation through Joint research project (SCOPES) [IZ73Z0 152420/1]
  • Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, USA

DOI: 10.1002/cbin.11084

ISSN: 1065-6995

PubMed: 30571852

WoS: 000456803100012

Scopus: 2-s2.0-85059636389
[ Google Scholar ]
3
4
URI
http://rimi.imi.bg.ac.rs/handle/123456789/952
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
Institut za medicinska istraživanja
TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Beleslin-Čokić, Bojana
AU  - Bjelica, Sunčica
AU  - Đikić, Dragoslava
AU  - Diklić, Miloš
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Santibanez, Juan
AU  - Noguchi, Constance T.
AU  - Čokić, Vladan
PY  - 2019
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/952
AB  - Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.
PB  - Wiley, Hoboken
T2  - Cell Biology International
T1  - IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling
EP  - 206
IS  - 2
SP  - 192
VL  - 43
DO  - 10.1002/cbin.11084
ER  - 
@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Beleslin-Čokić, Bojana and Bjelica, Sunčica and Đikić, Dragoslava and Diklić, Miloš and Leković, Danijela and Gotić, Mirjana and Santibanez, Juan and Noguchi, Constance T. and Čokić, Vladan",
year = "2019",
abstract = "Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.",
publisher = "Wiley, Hoboken",
journal = "Cell Biology International",
title = "IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling",
pages = "206-192",
number = "2",
volume = "43",
doi = "10.1002/cbin.11084"
}
Subotički, T., Mitrović-Ajtić, O., Beleslin-Čokić, B., Bjelica, S., Đikić, D., Diklić, M., Leković, D., Gotić, M., Santibanez, J., Noguchi, C. T.,& Čokić, V.. (2019). IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling. in Cell Biology International
Wiley, Hoboken., 43(2), 192-206.
https://doi.org/10.1002/cbin.11084
conv_4471
Subotički T, Mitrović-Ajtić O, Beleslin-Čokić B, Bjelica S, Đikić D, Diklić M, Leković D, Gotić M, Santibanez J, Noguchi CT, Čokić V. IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling. in Cell Biology International. 2019;43(2):192-206.
doi:10.1002/cbin.11084
conv_4471 .
Subotički, Tijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, Bjelica, Sunčica, Đikić, Dragoslava, Diklić, Miloš, Leković, Danijela, Gotić, Mirjana, Santibanez, Juan, Noguchi, Constance T., Čokić, Vladan, "IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling" in Cell Biology International, 43, no. 2 (2019):192-206,
https://doi.org/10.1002/cbin.11084 .,
conv_4471 .

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