Jihao Liu1, Zhuo Chen2, Mingdong Huang3, Shuzhi Tang1, Qianchao Wang4, Ping Hu4, Pranav Gupta5, Charles R Ashby5, Zhe-Sheng Chen6, Lei Zhang7. 1. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing, 100049, China. 2. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zchen@fjirsm.ac.cn. 3. College of Chemistry, Fuzhou University, Fuzhou, 350116, China. 4. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, Fujian 350002, China. 5. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, NY, 11439, USA. 6. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, NY, 11439, USA. Electronic address: chenz@stjohns.edu. 7. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian College, University of Chinese Academy of Sciences, Fuzhou, Fujian 350002, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zhangl@fjirsm.ac.cn.
Abstract
BACKGROUND: The protein plasminogen activator inhibitor-1 (PAI-1), an inhibitor specific for urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), has been shown to have a key role in cancer metastases. Currently, it is unknown as to whether the exocellular inhibition of PAI-1 can inhibit the migration of cancer cells. METHODS: By fusing the mutated serine protease domain (SPD) of uPA and human serum albumin (HSA), PAItrap3, a protein that traps PAI-1, was synthesized and experiments were conducted to determine if exocellular PAItrap3 attenuates PAI-1-induced cancer cell migration in vitro. RESULTS: PAItrap3 (0.8 μM) significantly inhibited the motility of MCF-7, MDA-MB-231, HeLa and 4T1 cancer cells, by 90%, 50%, 30% and 20%, respectively, without significantly altering their proliferation. The PAI-1-induced rearrangement of F-actin was significantly inhibited by PAItrap3, which produced a decrease in the number of cell protrusions by at least 20%. CONCLUSIONS: In vitro, PAItrap3 inhibited PAI-1-induced cancer cell migration, mainly through inhibiting the rearrangement of F-actin. Overall, these results, provided they can be extrapolated to humans, suggest that the PAItrap3 protein could be used as an exocellular inhibitor to attenuate cancer metastases.
BACKGROUND: The protein plasminogen activator inhibitor-1 (PAI-1), an inhibitor specific for urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), has been shown to have a key role in cancer metastases. Currently, it is unknown as to whether the exocellular inhibition of PAI-1 can inhibit the migration of cancer cells. METHODS: By fusing the mutated serine protease domain (SPD) of uPA and humanserum albumin (HSA), PAItrap3, a protein that traps PAI-1, was synthesized and experiments were conducted to determine if exocellular PAItrap3 attenuates PAI-1-induced cancer cell migration in vitro. RESULTS: PAItrap3 (0.8 μM) significantly inhibited the motility of MCF-7, MDA-MB-231, HeLa and 4T1cancer cells, by 90%, 50%, 30% and 20%, respectively, without significantly altering their proliferation. The PAI-1-induced rearrangement of F-actin was significantly inhibited by PAItrap3, which produced a decrease in the number of cell protrusions by at least 20%. CONCLUSIONS: In vitro, PAItrap3 inhibited PAI-1-induced cancer cell migration, mainly through inhibiting the rearrangement of F-actin. Overall, these results, provided they can be extrapolated to humans, suggest that the PAItrap3 protein could be used as an exocellular inhibitor to attenuate cancer metastases.