A novel target for treatment of chordoma: signal transducers and activators of transcription 3.
A major obstacle in the effective treatment of chordoma is that there are no identifiable biomarkers capable of predicting prognosis. Recent research has indicated that signal transducers and activators of transcription (Stat3) may be an important prognostic marker in some cancers, but its role in chordoma tumors has not been elucidated. In this study, the expression of Stat3 was evaluated in chordoma tissue microarray that contains 70 chordoma samples. Cells in the tissue microarray showed nuclear staining for phosphorylated Stat3 in all instances. The level of phosphorylated Stat3 expression correlated with the survival and severity of the disease. Three chordoma cell lines were exposed to SD-1029, a novel inhibitor of Stat3 activation. MTT assay showed that the growth of all chordoma cell lines was inhibited by SD-1029. The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029. The cytotoxicity of the combination of SD-1029 and chemotherapeutic drugs is significantly better than either agent alone. Phosphorylation of Stat3 in chordoma cells in vitro and cellular proliferation in three-dimensional culture were inhibited by SD-1029. In conclusion, the Stat3 pathway is constitutively activated in chordomas and the level of expression may serve as a predictor for prognosis. Blockade of the Stat3 pathway represents a potential strategy for future treatment.
Yang
Cao
C
Department of Orthopaedic Surgery, Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Schwab
Joseph H
JH
Schoenfeld
Andrew J
AJ
Hornicek
Francis J
FJ
Wood
Kirkham B
KB
Nielsen
G Petur
GP
Choy
Edwin
E
Mankin
Henry
H
Duan
Zhenfeng
Z
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002817:Chordoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D014966:Xanthenes / Q000008:administration & dosage / Q000494:pharmacology
C516783:SD 1029; D050796:STAT3 Transcription Factor; D014966:Xanthenes; D004317:Doxorubicin; D002945:Cisplatin