ABSTRACT
BACKGROUND: Overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET (Bromodomain and extraterminal domain family) bromodomain (BRDs) inhibitor, has been found to suppress tumour progression in several cancer cell types. RESULTS: Using a panel of ovarian cancer cell lines and primary cell cultures from human ovarian cancer ascites, we demonstrated that JQ1 significantly suppressed cell proliferation and induced apoptosis in an ovarian cancer cell by targeting BRD4 and c-Μyc. In addition, JQ1 sensitized ovarian cancer cells to cisplatin, the most commonly used chemotherapeutic agent in ovarian cancer. Importantly, this effect was observed in ovarian cells, which exhibited resistance to cisplatin alone. Finally, we show that JQ1 interacts with the JAK-STAT signalling pathway, a pathway important in supporting ovarian cancer cell survival by suppressing or inducing genes involved in cell survival and apoptosis, respectively. CONCLUSION: Our data, taken together, suggest that JQ1 is an attractive antitumour candidate for further investigation in the treatment of ovarian cancer, as it associates with cell proliferation, apoptosis, and alterations in the JAK-STAT signalling pathway, especially in patients with a platinum-resistant profile or in patients with relapsed disease.
Subject(s)
Azepines/pharmacology , Cell Proliferation/drug effects , Cisplatin/pharmacology , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Triazoles/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Cell Survival/drug effects , Cell Survival/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Janus Kinases/genetics , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , STAT Transcription Factors/genetics , Signal Transduction/genetics , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis in ovarian cancer, among other tumor types, as it leads to new blood vessel formation. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Growth factors have been identified to play key roles in driving angiogenesis and, thus, the formation of new blood vessels that assist in "feeding" cancer. Such molecules include the vascular endothelial growth factor (VEGF), the platelet derived growth factor (PDGF), the fibroblast growth factor (FGF), and the angiopoietin/Tie2 receptor complex. These proteins are key players in complex molecular pathways within the tumor cell and they have been in the spotlight of the development of anti-angiogenic molecules that may act as stand-alone therapeutics, or in concert with standard treatment regimes such as chemotherapy. The pathways involved in angiogenesis and molecules that have been developed in order to combat angiogenesis are described in this paper.
