Therapeutic suppression of constitutive and inducible JAK\STAT activation in head and neck squamous cell carcinoma.
The oncogenic role of STAT3 has been elucidated in a number of human malignancies including leukemia, lymphoma, malignant glioma and cancers of the breast, lung, and head and neck (HNSCC). Here we show that WP1066 has profound anti-neoplastic effects in HNSCC, mediated in part by suppression of JAK2-STAT3 signaling. WP1066 inhibited constitutive and inducible STAT3 phosphorylation in both dose- and time-dependant manners. Further, the nuclear translocation of STAT3 was completely inhibited, resulting in decreased DNA binding activity. In vivo testing of WP1066 in a nude mouse orthotopic model of HNSCC demonstrated significant anti-tumor effects, with histological evidence of decreased cellular proliferation and angiogenesis. Collectively, these data suggest that WP1066 suppresses squamous cell carcinoma cell growth, in part through its effects on JAK-STAT pathways, and establishes this small molecule as potentially efficacious agent in the treatment of HNSCC.
Kupferman
Michael E
ME
Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. mekupfer@mdanderson.org
Jayakumar
Arumugam
A
Zhou
Ge
G
Xie
Tong
T
Dakak-Yazici
Yasemin
Y
Zhao
Mei
M
Ju
Jun
J
Mandal
Mahitosh
M
Jasser
Samar
S
Madden
Timothy
T
Myers
Jeffrey N
JN
Priebe
Waldemar
W
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; D042461:Vascular Endothelial Growth Factor A; C519885:WP1066