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An experimental study to investigate the activation of Src/Stat3 pathways in chordomas and blockage of this pathway as a potential strategy for chordoma treatment.To investigate the activation of Src/Stat3 pathway in chordomas cells and to determine the efficiency of inhibiting this pathway by 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-methyl ester (CDDO-Me) as a potential chemotherapeutic agent for chordoma treatment.The advent of molecularly targeted therapies has raised interest for their use in the treatment of chordomas. Unfortunately, the current understanding of molecular markers in chordomas is limited. Constitutive activation of Stat3 is a common finding in a wide spectrum of human cancers. The function of Stat3 pathway in chordomas has not been elucidated.The expression of key components of the Src/Stat3 signaling cascade was evaluated by Western blot in chordoma tissues and chordoma cell lines. The effects of CDDO-Me on chordoma cell growth were evaluated in these chordoma cell lines by MTT assay. The expression of key components of the Src/Stat3 signaling cascade and poly (ADP-ribose) polymerase cleavage in these CDDO-Me treated cells were analyzed by Western blot and immunofluorescence. Furthermore, the synergistic effect of CDDO-Me on cisplatin and doxorubicin-induced cytotoxicity was evaluated by MTT. Finally, chordoma cells were grown in a 3-dimensional (3D) culture and treated with CDDO-Me.The key components of the Src/Stat3 signaling cascade, including Stat3, pStat3, Src, pSrc, Bcl-xL, and Myeloid Cell Leukemia-1, were all highly expressed in chordomas. Expression of the key components of the Src/Stat3 signaling cascade was inhibited in chordoma cells after treatment with CDDO-Me. The growth of chordoma cells was inhibited and apoptosis associated poly (ADP-ribose) polymerase cleavage was detected after treatment with CDDO-Me. Additionally, CDDO-Me has a synergistic effect on cisplatin or doxorubicin-induced chordoma cell death (P < 0.001). Finally, expression of pSrc and pStat3 and chordoma cell growth was inhibited by treatment of CDDO-Me using 3D culture.The Src/Stat3 signaling pathway was activated in chordomas. Blockage of Src/Stat3 pathway by CDDO-Me is a potential strategy for chordoma treatment and may be focus for future research.