Faculty Information |
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Article types | Original article |
Language | English |
Refereed paper | Refereed |
Title | Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma. |
Journal | Formal name:Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Abbreviation:J Thorac Oncol ISSN code:1556-1380(Electronic)1556-0864(Linking) |
Domestic / Foregin | Foregin |
Volume, Number, Page | 12(3),pp.477-490 |
Papers・Author | Cho Hiroyuki, Matsumoto Seiji, Fujita Yoshiko, Kuroda Ayumi, Menju Toshi, Sonobe Makoto, Kondo Nobuyuki, Torii Ikuko, Nakano Takashi, Lara Primo N, Gandara David R, Date Hiroshi, Hasegawa Seiki |
Publication date | 2017/03 |
Papers・Description | INTRODUCTION:Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM.METHODS:We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model.RESULTS:Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1]component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone.CONCLUSIONS:Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted. |
DOI | 10.1016/j.jtho.2016.10.023 |
PMID | 27867002 |