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Gritsina G , Xiao F , O'Brien SW , Gabbasov R , Maglaty MA , Xu RH , Thapa RJ , Zhou Y , Nicolas E , Litwin S , Balachandran S , Sigal LJ , Huszar D , Connolly DC
Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth
Mol Cancer Ther. 2015 Apr;14(4) :1035-47
PMID: 25646015 PMCID: PMC4394029 URL: https://www.ncbi.nlm.nih.gov/pubmed/25646015
AbstractOvarian carcinoma is the fifth leading cause of death among women in the United States. Persistent activation of STAT3 is frequently detected in ovarian carcinoma. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor, and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses antitumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on ovarian carcinoma cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small-molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration, and adhesion of ovarian carcinoma cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity, and immune cell populations in a transgenic mouse model of ovarian carcinoma. AZD1480 treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured ovarian carcinoma cells and ovarian tumor growth rate, volume, and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal TME of tumor-bearing mice than control mice. Taken together, our results show pharmacologic inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
NotesGritsina, Galina Xiao, Fang O'Brien, Shane W Gabbasov, Rashid Maglaty, Marisa A Xu, Ren-Huan Thapa, Roshan J Zhou, Yan Nicolas, Emmanuelle Litwin, Samuel Balachandran, Siddharth Sigal, Luis J Huszar, Dennis Connolly, Denise C P30 CA006927/CA/NCI NIH HHS/United States R01 CA136596/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Mol Cancer Ther. 2015 Apr;14(4):1035-47. doi: 10.1158/1535-7163.MCT-14-0800. Epub 2015 Feb 2.