Enhanced activation of STAT3 in ascites-derived recurrent ovarian tumors: inhibition of cisplatin-induced STAT3 activation reduced tumorigenicity of ovarian cancer by a loss of cancer stem cell-like characteristics
Journal Title
J Cancer Stem Cell Res
Publication Type
Journal Article
Abstract
Chemotherapy resistance is a major obstacle for the treatment of ovarian cancer patients. Combination of drugs which can exert synergistic effect can be a promising strategy to overcome this resistance. In this study, we report significantly enhanced activation of Janus kinase 2 (JAK2) and its downstream target signal transducer and activation of transcription 3 (STAT3) in tumor cells isolated from the ascites of recurrent ovarian cancer patients (CR) compared to tumor cells isolated from the ascites of chemonaïve patients (CN). Enhanced activation of JAK2 and STAT3 in the tumor cells of recurrent patients coincided with the in vitro activation of JAK2 and STAT3 pathway in cisplatin-surviving ovarian cancer cell lines. This coincided with the emergence of cancer stem cell (CSC)-like characteristics in response to cisplatin treatment in ovarian cancer cell lines. Both cisplatin-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 in vitro. Subsequent, in vivo transplantation of cisplatin and CYT387 in vitro treated ovarian cancer cells in mice resulted in a significantly reduced tumor burden compared to that observed in mice injected with cisplatin only-treated cells. In vitro analysis of tumor xenografts at the protein level demonstrated a loss of CSC-like (CD117 and Oct4) and tumorigenic (CA125) markers in cisplatin and CYT387-treated cell-derived xenografts, compared to cisplatin only-treated cell-derived xenografts. These results were consistent with a significantly reduced activation of JAK2 and STAT3 in cisplatin and CYT387-treated cell-derived xenografts compared to cisplatin only-treated cell derived xenografts. These data suggest that the inhibition of the JAK2/STAT3 pathway by the addition of CYT387 in combination with cisplatin may have important implications for ovarian cancer patients who are treated with platinum-based first line therapies.
Publisher
JCSCR
WEHI Research Division(s)
Chemical Biology
Rights Notice
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Creation Date: 2015-03-24 02:23:27
Last Modified: 2015-05-12 09:11:13
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