TM5614, an Inhibitor of Plasminogen Activator Inhibitor-1, Exerts an Antitumor Effect on Chronic Myeloid Leukemia

• Main Authors: Fujiwara, T. (Author), Fukuhara, N. (Author), Harigae, H. (Author), Ichikawa, S. (Author), Kato, H. (Author), Miyata, T. (Author), Ochi, T. (Author), Onishi, Y. (Author), Ono, K. (Author), Onodera, K. (Author), Sasaki, K. (Author), Yokoyama, H. (Author)
• Format: Article
• Language: English
• Published: NLM (Medline) 2022
• Subjects: apoptosis; Apoptosis; chronic myeloid leukemia; drug resistance; Drug Resistance, Neoplasm; furin; Furin; FURIN; genetics; human; Humans; K-562 cell line; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; matrix metalloproteinase 14; Matrix Metalloproteinase 14; messenger RNA; NOTCH1 signaling; pathology; plasminogen activator inhibitor 1; Plasminogen Activator Inhibitor 1; plasminogen activator inhibitor-1; protein kinase inhibitor; Protein Kinase Inhibitors; RNA, Messenger; TM5614
• Online Access: View Fulltext in Publisher

 Chronic myeloid leukemia (CML) is triggered by t(9;22)(q34;q11.2) translocation, leading to the formation of the BCR-ABL1 fusion gene. Although the development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has dramatically improved the prognosis of CML, the disease could often relapse, presumably because leukemic stem cell fraction of CML (CML-LSC) may reside in specific niches, and also acquire an ability to resist the cytotoxic agents. Recently a study indicated that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1, also known as SERPINE1) would cause detachment of CML-LSCs from their niche by inducing maturation of membrane-type matrix metalloprotease-1 (MT1-MMP), leading to increased susceptibility of CML-LSCs against TKIs. However, the direct antitumor effect of PAI-1 inhibition in CML remains unclear. Because PAI-1 mRNA expression was lower in CML cell line (K562) than bone marrow mononuclear cells derived from CML patients, we established K562 cell clones stably expressing exogenous PAI-1 (K562/PAI-1). We found that TM5614 treatment significantly suppressed cell proliferation and induced apoptosis in K562/PAI-1 cells, accompanied by increased activity of Furin protease, which is a known target of PAI-1. Besides processing mature MT1-MMP, Furin is in charge of cleaving the NOTCH receptor to form a heterodimer before exporting it to the cell surface membrane. In K562/PAI-1 cells, TM5614 treatment increased NOTCH1 intracellular domain (NICD) protein expression as well as NOTCH1 target of HEY1 mRNA levels. Finally, forced expression of either Furin or NICD in K562/PAI-1 cells significantly inhibited cell proliferation and induced apoptosis. Collectively, PAI-1 inhibition may have an antitumor effect by modulating the Furin/NICD pathway.