Inhibition of PAR-1 Receptor Signaling by Enoxaparin Reduces Cell Proliferation and Migration in A549 Cells

• Published in: Anticancer research Vol. 39; no. 10; pp. 5297 - 5310
• Main Authors: ALTURKISTANI, AZHAAR, GHONEM, NISANNE, POWER-CHARNITSKY, VERNA-ANN, PINO-FIGUEROA, ALEJANDRO, MIGLIORE, MATTIA M.
• Format: Journal Article
• Language: English
• Published: Athens International Institute of Anticancer Research 01-10-2019
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; AKT protein; Anticancer properties; Antitumor activity; Apoptosis; Cell adhesion & migration; Cell cycle; Cell growth; Cell migration; Cell proliferation; Chemotherapy; Down-regulation; Doxorubicin; Evaluation; Gelatinase A; Heparin; Immunoblotting; Lung cancer; MAP kinase; Molecular weight; Par-1 protein; Proteinase-activated receptor 1; Signaling; siRNA
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.13723

Background/Aim: Low-molecular weight heparins (LMWHs) may possess putative antitumoral properties; however, the underlying mechanism(s) remains elusive. We evaluated the antiproliferative and antimigratory effects of enoxaparin (a LMWH) in lung adenocarcinoma A549 cells, and assessed the possible mechanism involved, and the effect on doxorubicin's efficacy. Materials and Methods: Proliferation and migration were evaluated using BrdU and transwell assays, respectively. Immunoblotting was used to measure PAR-1, PAR-2, MMP-2, ERK1/2 and Akt proteins. Apoptosis and cell cycle studies examined the combined effect of enoxaparin and doxorubicin. Results: Enoxaparin inhibited A549 cell proliferation and migration. Following PAR-1 gene knock down, enoxaparin's effect on A549 cell proliferation was diminished compared to scrambled siRNA. Our experiments verified that enoxaparin-mediated down-regulation of MAPK and PI3K, reduced MMP-2 expression and inhibited A549 cell migration. Additionally, enoxaparin increased doxorubicin's efficacy by enhancing apoptosis, while no effect on cell-cycle progression was observed. Conclusion: Results suggest that the anticancer activity of enoxaparin in A549 cells was mediated by the interference of two major PAR-1 downstream signaling pathways, MAPK/ERK and PI3K/Akt, which in turn inhibit proliferation and migration. Therefore, enoxaparin may be promising as an adjunct to traditional chemotherapy for lung cancer and warrants further investigation.