Repurposing Tranexamic Acid as an Anticancer Agent.
Repurposing Tranexamic Acid as an Anticancer Agent.
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DOI：
10.3389/fphar.2021.792600
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发表时间：
2021
影响因子：
5.6
通讯作者：
Law BK
中科院分区：
文献类型：
--
作者：
Law ME;Davis BJ;Ghilardi AF;Yaaghubi E;Dulloo ZM;Wang M;Guryanova OA;Heldermon CD;Jahn SC;Castellano RK;Law BK
氨甲环酸（TA）是一种临床使用的抗纤溶药物，作为一种赖氨酸模拟物，阻断纤溶酶原与纤溶酶原激活剂的结合，阻止纤溶酶原转化为其蛋白水解激活形式——纤溶酶。先前的研究表明，TA可能通过阻断细胞外纤溶蛋白的形成而具有抗癌活性。纤溶蛋白介导的CDCP1蛋白的裂解可能通过几个下游途径增加其致癌功能。本研究的结果表明，TA阻断了纤溶酶介导的癌蛋白CDCP1细胞外结构域的切除。体外研究表明，TA降低了多种人类和小鼠癌细胞系的活力，乳腺肿瘤生长研究表明，TA降低了体内肿瘤的生长。基于TA模拟赖氨酸和精氨酸的能力，我们假设TA可能干扰涉及赖氨酸/精氨酸丰富蛋白序列的多个过程，并且除了阻断细胞外纤溶蛋白的产生外，TA还可能改变细胞内信号通路。事实上，ta介导的肿瘤细胞活力的抑制与多种生化作用有关，包括抑制蛋白质合成，降低STAT3和S6K1的活化磷酸化，降低MYC癌蛋白的表达，抑制Lys乙酰化。此外，TA抑制癌细胞对赖氨酸和精氨酸的摄取。这些发现表明，TA或TA类似物可能作为先导化合物，并激发通过模仿赖氨酸和精氨酸发挥作用的新型抗癌药物的产生。
Tranexamic Acid (TA) is a clinically used antifibrinolytic agent that acts as a Lys mimetic to block binding of Plasminogen with Plasminogen activators, preventing conversion of Plasminogen to its proteolytically activated form, Plasmin. Previous studies suggested that TA may exhibit anticancer activity by blockade of extracellular Plasmin formation. Plasmin-mediated cleavage of the CDCP1 protein may increase its oncogenic functions through several downstream pathways. Results presented herein demonstrate that TA blocks Plasmin-mediated excision of the extracellular domain of the oncoprotein CDCP1. In vitro studies indicate that TA reduces the viability of a broad array of human and murine cancer cell lines, and breast tumor growth studies demonstrate that TA reduces cancer growth in vivo. Based on the ability of TA to mimic Lys and Arg, we hypothesized that TA may perturb multiple processes that involve Lys/Arg-rich protein sequences, and that TA may alter intracellular signaling pathways in addition to blocking extracellular Plasmin production. Indeed, TA-mediated suppression of tumor cell viability is associated with multiple biochemical actions, including inhibition of protein synthesis, reduced activating phosphorylation of STAT3 and S6K1, decreased expression of the MYC oncoprotein, and suppression of Lys acetylation. Further, TA inhibited uptake of Lys and Arg by cancer cells. These findings suggest that TA or TA analogs may serve as lead compounds and inspire the production of new classes of anticancer agents that function by mimicking Lys and Arg.
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影响因子：
8
作者：
通讯作者：
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影响因子：
1.1
作者：
Atreya S
通讯作者：
Atreya S
影响因子：
4.8
作者：
Dennis, PB;Pullen, N;Thomas, G
通讯作者：
Thomas, G
影响因子：
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作者：
Ferreira RB;Wang M;Law ME;Davis BJ;Bartley AN;Higgins PJ;Kilberg MS;Santostefano KE;Terada N;Heldermon CD;Castellano RK;Law BK
通讯作者：
Law BK
影响因子：
4.8
作者：
He, Yaowu;Wortmann, Andreas;Hooper, John D.
通讯作者：
Hooper, John D.