Mediatory role of BLT2 in the proliferation of KRAS mutant colorectal cancer cells

https://doi.org/10.1016/j.bbamcr.2018.12.006Get rights and content
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Highlights

  • BLT2 is up-regulated in KRAS mutant colorectal cancer cells.

  • BLT2 inhibition suppressed the proliferation of KRAS mutant colorectal cancer cells.

  • 5-/12-LO and its product leukotriene B4/12(S)-HETE are also associated with the proliferation.

  • PI3K/Akt lies downstream of BLT2 to mediate the proliferation of KRAS mutant colorectal cancer cells.

  • BLT2-PI3K/Akt cascade mediates the production of cyclin D1, thereby regulating cell cycle progression.

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 B4 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.

Abbreviations

BLT
leukotriene B4 receptor
LO
lipoxygenase
LT
leukotriene
HETE
hydroxyeicosatetraenoic acid
CRC
colorectal cancer
PI3K/Akt
phosphoinositide 3‑kinase/protein kinase B
siRNA
small interfering RNA

Keywords

KRAS
LOVO
SW480
Colorectal cancer
Proliferation
BLT2
LTB4
PI3K
Akt

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