Title

Investigating the Antagonistic Role of Constitutively Activated and Stabilized TAFI(a) on Breast Cancer Cell Metastasis

Type of Proposal

Oral presentation

Start Date

29-3-2016 2:30 PM

End Date

29-3-2016 3:50 PM

Faculty

Faculty of Science

Faculty Sponsor

UWill Discover

Abstract

Metastasis of a malignant tumor is one of the leading causes of death in patients with cancer. The plasminogen activation system plays an important role in the metastatic process. The conversion of plasminogen to plasmin is catalyzed by plasminogen binding to its respective plasminogen receptor on the cellular surface. Plasmin and matrix-metalloproteinases (MMPs) facilitate extracellular matrix remodelling, consequentially enhancing the invasion and migration of cancer cells. Thrombin-activatable fibrinolysis inhibitor (TAFI), a plasma zymogen, plays a pivotal role in decreasing cancer cell metastasis once activated. TAFI is activated through proteolytic cleavage of an activation domain by thrombin, plasmin, or most effectively thrombin in complex with thrombomodulin. Thromobomodulin has been shown to be expressed in cancer cells and is inversely proportional to malignancy. Activated TAFI (TAFIa) exerts basic carboxypeptidase activity with the capacity to cleave carboxyl-terminal lysine residues on plasminogen binding present on the cell-surface receptors. Importantly, TAFIa is intrinsically unstable with a half-life of only 8-15 minutes at body temperature. The intrinsic instability and reliance on physiological activators regulates the recently discovered contribution of TAFIa in a tumor microenvironment. Therefore, the construction of a stabilized and constitutively activated variant of TAFI(a) may represent a novel therapeutic strategy to prevent breast cancer cell metastasis.

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Mar 29th, 2:30 PM Mar 29th, 3:50 PM

Investigating the Antagonistic Role of Constitutively Activated and Stabilized TAFI(a) on Breast Cancer Cell Metastasis

Metastasis of a malignant tumor is one of the leading causes of death in patients with cancer. The plasminogen activation system plays an important role in the metastatic process. The conversion of plasminogen to plasmin is catalyzed by plasminogen binding to its respective plasminogen receptor on the cellular surface. Plasmin and matrix-metalloproteinases (MMPs) facilitate extracellular matrix remodelling, consequentially enhancing the invasion and migration of cancer cells. Thrombin-activatable fibrinolysis inhibitor (TAFI), a plasma zymogen, plays a pivotal role in decreasing cancer cell metastasis once activated. TAFI is activated through proteolytic cleavage of an activation domain by thrombin, plasmin, or most effectively thrombin in complex with thrombomodulin. Thromobomodulin has been shown to be expressed in cancer cells and is inversely proportional to malignancy. Activated TAFI (TAFIa) exerts basic carboxypeptidase activity with the capacity to cleave carboxyl-terminal lysine residues on plasminogen binding present on the cell-surface receptors. Importantly, TAFIa is intrinsically unstable with a half-life of only 8-15 minutes at body temperature. The intrinsic instability and reliance on physiological activators regulates the recently discovered contribution of TAFIa in a tumor microenvironment. Therefore, the construction of a stabilized and constitutively activated variant of TAFI(a) may represent a novel therapeutic strategy to prevent breast cancer cell metastasis.