Modulation of Janus kinase 2 by cisplatin in cancer cells.
Constitutive activation of Janus kinases (JAKs) is frequently detected in various human cancers. The activation of JAKs results in the phosphorylation and activation of signal transducers and activators of transcription (STATs). The constitutive activation of JAK/STAT pathway may play an important role in growth and survival of human cancer cells. In this study, we examined whether a chemotherapeutic agent cisplatin could inhibit the JAK/STAT pathway. In ovarian cancer and sarcoma cells that express constitutively active JAK2, cisplatin significantly inhibited tyrosine phosphorylation and kinase activity of JAK2 in a dose- and time-dependent manner. Meanwhile, cisplatin also inhibited Stat3 tyrosine phosphorylation and down-regulated BcL-XL anti-apoptotic protein in the cancer cells tested. In leukemia cells expressing high level of TEL-JAK2 fusion protein, cisplatin dramatically inhibited tyrosine phosphorylation of TEL-JAK2 as well. Furthermore, our results have shown that down-regulation of JAK2 by cisplatin might be through modulation of a tyrosine phosphatase SHP-1 but not SOCS family members. Taken together, our observations demonstrated that cisplatin down-regulated the JAK/STAT pathway through de-phosphorylation of JAK/STAT in cancer cells.
Song
Hui
H
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0936, USA.
Sondak
Vernon K
VK
Barber
Dwayne L
DL
Reid
Thomas J
TJ
Lin
Jiayuh
J
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D051020:bcl-X Protein; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D015514:Oncogene Proteins, Fusion; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014443:Tyrosine; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C108944:SOCS1 protein, human; C494086:STAT3 protein, human; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C507924:JAK2 protein, human; C509249:PTPN6 protein, human