IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling
2019
Autori
Subotički, TijanaMitrović-Ajtić, Olivera
Beleslin-Čokić, Bojana
Bjelica, Sunčica
Đikić, Dragoslava
Diklić, Miloš
Leković, Danijela
Gotić, Mirjana
Santibanez, Juan F.
Noguchi, Constance T.
Čokić, Vladan
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Ključne reči:
cell cycle / ERK1/2 signaling / inflammation / JAK1/2 inhibition / myeloproliferative neoplasmIzvor:
Cell Biology International, 2019, 43, 2, 192-206Izdavač:
- Wiley, Hoboken
Finansiranje / projekti:
- Ispitivanje patogeneze hematoloških maligniteta (RS-MESTD-Basic Research (BR or ON)-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
Institucija/grupa
Institut za medicinska istraživanjaTY - 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 F. 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 F. 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. F., 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
Subotički T, Mitrović-Ajtić O, Beleslin-Čokić B, Bjelica S, Đikić D, Diklić M, Leković D, Gotić M, Santibanez JF, 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 .
Subotički, Tijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, Bjelica, Sunčica, Đikić, Dragoslava, Diklić, Miloš, Leković, Danijela, Gotić, Mirjana, Santibanez, Juan F., 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 . .