1. IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling.
- Author
-
Subotički T, Mitrović Ajtić O, Beleslin-Čokić BB, Bjelica S, Djikić D, Diklić M, Leković D, Gotić M, Santibanez JF, Noguchi CT, and Čokić VP
- Subjects
- Adult, Aged, Antigens, CD34 metabolism, Cell Line, Tumor, Female, Granulocytes cytology, Granulocytes drug effects, Granulocytes metabolism, Humans, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 genetics, Male, Middle Aged, Myeloproliferative Disorders metabolism, Nitriles, Phosphorylation drug effects, Polymorphism, Single Nucleotide, Pyrazoles pharmacology, Pyrimidines, S Phase Cell Cycle Checkpoints drug effects, STAT Transcription Factors metabolism, DNA Replication drug effects, Interleukin-6 pharmacology, Janus Kinase 1 metabolism, Janus Kinase 2 metabolism, MAP Kinase Signaling System drug effects, Myeloproliferative Disorders pathology
- 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., (© 2018 International Federation for Cell Biology.)
- Published
- 2019
- Full Text
- View/download PDF