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Mediatory role of BLT2 in the proliferation of KRAS mutant colorectal cancer cells.
- Source :
-
Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2019 Mar; Vol. 1866 (3), pp. 329-336. Date of Electronic Publication: 2018 Dec 13. - Publication Year :
- 2019
-
Abstract
- Inflammatory lipid mediators play various roles in colorectal cancer progression through complex pathways. However, the mechanism by which lipoxygenase-derived inflammatory lipid mediators contribute to colorectal cancer progression remains elusive. In this study, we found that BLT2, a cell surface GPCR for leukotriene B <subscript>4</subscript> and 12‑hydroxyeicosatetraenoic acid, is highly upregulated in KRAS mutant LOVO and SW480 colorectal cancer cells and plays critical roles in mediating proliferation through activation of phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) and subsequent upregulation of cyclin D1. Exposure to BLT2 siRNA or LY255283, a specific BLT2 inhibitor, clearly suppressed the proliferation of KRAS mutant colorectal cancer cells and markedly increased cell cycle arrest by downregulating the PI3K/Akt-cyclin D1 cascade. Xenograft tumor formation by LOVO and SW480 cells in athymic mice was also substantially reduced by treatment with the BLT2 inhibitor in vivo. Together, our study demonstrates that BLT2 is necessary for the proliferation of LOVO and SW480 cells and thus may be a potential therapeutic target for the treatment of KRAS mutant colorectal cancer.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Colorectal Neoplasms drug therapy
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Female
Humans
Hydroxyeicosatetraenoic Acids pharmacology
Leukotriene B4 pharmacology
Mice
Mice, Inbred BALB C
Mice, Nude
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
Proto-Oncogene Proteins p21(ras) genetics
Receptors, Leukotriene B4 antagonists & inhibitors
Receptors, Leukotriene B4 genetics
Signal Transduction
Tetrazoles pharmacology
Up-Regulation
Xenograft Model Antitumor Assays
Colorectal Neoplasms metabolism
Proto-Oncogene Proteins p21(ras) metabolism
Receptors, Leukotriene B4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-2596
- Volume :
- 1866
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular cell research
- Publication Type :
- Academic Journal
- Accession number :
- 30553812
- Full Text :
- https://doi.org/10.1016/j.bbamcr.2018.12.006