دورية أكاديمية
Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth.
| العنوان: | Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth. |
|---|---|
| المؤلفون: | Gritsina G; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Xiao F; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., O'Brien SW; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Gabbasov R; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Kazan (Volga Region) Federal University, Kazan, Russia., Maglaty MA; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Xu RH; Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Thapa RJ; Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Zhou Y; Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Nicolas E; Genomics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Litwin S; Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Balachandran S; Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Sigal LJ; Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Huszar D; AstraZeneca Oncology iMed, Waltham, Massachusetts., Connolly DC; Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Denise.Connolly@fccc.edu. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2015 Apr; Vol. 14 (4), pp. 1035-47. Date of Electronic Publication: 2015 Feb 02. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Analgesics/*pharmacology , Janus Kinases/*metabolism , Ovarian Neoplasms/*metabolism , STAT3 Transcription Factor/*metabolism , Signal Transduction/*drug effects, Analgesics/administration & dosage ; Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cluster Analysis ; Disease Models, Animal ; Female ; Gene Expression ; Gene Expression Profiling ; Humans ; Integrin alphaVbeta3/genetics ; Integrin alphaVbeta3/metabolism ; Matrix Metalloproteinases/metabolism ; Mice ; Mice, Transgenic ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Pyrazoles/administration & dosage ; Pyrazoles/pharmacology ; Pyrimidines/administration & dosage ; Pyrimidines/pharmacology ; Xenograft Model Antitumor Assays |
| مستخلص: | Ovarian 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. (©2015 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | P30 CA006927 United States CA NCI NIH HHS; R01 AI065544 United States AI NIAID NIH HHS; R01 CA136596 United States CA NCI NIH HHS; T32 CA009035 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (AZD 1480) 0 (Analgesics) 0 (Integrin alphaVbeta3) 0 (Pyrazoles) 0 (Pyrimidines) 0 (STAT3 Transcription Factor) EC 2.7.10.2 (Janus Kinases) EC 3.4.24.- (Matrix Metalloproteinases) |
| تواريخ الأحداث: | Date Created: 20150204 Date Completed: 20160126 Latest Revision: 20240514 |
| رمز التحديث: | 20240514 |
| مُعرف محوري في PubMed: | PMC4394029 |
| DOI: | 10.1158/1535-7163.MCT-14-0800 |
| PMID: | 25646015 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
|---|---|
| DOI: | 10.1158/1535-7163.MCT-14-0800 |