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Abstract
Plasminogen activator inhibitor (PAI)-1 is predictive of poor outcome in several types of cancer. The present study investigated the biological role for PAI-1 in ovarian cancer and potential of targeted pharmacotherapeutics. In patients with ovarian cancer, PAI-1 mRNA expression in tumor tissues was positively correlated with poor prognosis. To determine the role of PAI-1 in cell proliferation in ovarian cancer, the effects of PAI-1 inhibition were examined in PAI-1-expressing ovarian cancer cells. PAI-1 knockdown by small interfering RNA resulted in significant suppression of cell growth accompanied with G2/M cell cycle arrest and intrinsic apoptosis. Similarly, treatment with the small molecule PAI-1 inhibitor TM5275 effectively blocked cell proliferation of ovarian cancer cells that highly express PAI-1. Together these results suggest that PAI-1 promotes cell growth in ovarian cancer. Interestingly, expression of PAI-1 was increased in ovarian clear cell carcinoma compared with that in serous tumors. Our results suggest that PAI-1 inhibition promotes cell cycle arrest and apoptosis in ovarian cancer and that PAI-1 inhibitors potentially represent a novel class of anti-tumor agents.
Disclosure of Potential Conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank the laboratory members of the Biomedical Research Unit of Tohoku University Hospital, and the Departments of Microbiology and Immunology, and Obstetrics and Gynecology (Tohoku University, Sendai, Japan) for critical discussion.
Funding
This study was supported in part by JSPS KAKENHI Grants (23790366, to K.K., 24390375 to N.Y. and 23791801 to M.T), a Health Labor Sciences Research Grant (201221019A to N.Y.), the Kurokawa Cancer Research Foundation (M.T.), the Japan Society of Gynecologic Oncology (M.T.), the Foundation for Promotion of Cancer Research (M.T.), and Tohoku University Graduate School of Medicine United Center for Advanced Research and Translational Medicine (M.T.).