Blockade of Leukotriene B4 Signaling Pathway Induces Apoptosis and Suppresses Cell Proliferation in Colon Cancer

Abstract

Abstract. We investigated whether leukotriene B 4 (LTB 4 ) and its signaling pathway play an important role in the progression of human colon cancer via a direct stimulation of cancer cell proliferation. Remarkable expression of LTB 4 receptor 1 (BLT1) in human colon cancer tissues was detected by immunohistochemistry, and Western blot analysis revealed the BLT1 expression in cultured human colon cancer cell lines, Caco2 and HT29. The 5-lipoxygenase inhibitor AA-861 and LTB 4 -receptor antagonist U75302 showed negative effects on survival and proliferation of both Caco2 and HT-29 cells. The inhibition of cell proliferation is due to the apoptosis because nuclear condensation and increased annexin V expression were observed in the cells treated with AA-861 and U75302. Knockdown of BLT1 by small interfering RNA caused the suppression of BLT1 protein, resulting in the inhibition of cancer cell proliferation. Blockade of BLT1 by the receptor antagonist significantly suppresses the LTB 4 -stimulated extracellular signal-regulated kinase (ERK) activation in colon cancer cells. These results indicate that the blockade of the LTB 4 -signaling pathway induces apoptosis via the inhibition of ERK activation in colon cancer cells. The LTB 4 -signaling pathway might be a new therapeutic target for colon cancer.

Role of eicosanoids on intestinal epithelial homeostasis

“…High expression of the BLT 1 receptor [19] and the CystLT 1 receptor was detected in human colon cancer tissues, whereas CysLT 2 receptor expression was reduced in colon cancer and was associated with poor prognosis, due to its capacity to induce differentiation and growth inhibition [18]. Thus, the CysLT 2 receptor could have more anti-tumorigenic activity than the CysLT 1 receptor in intestinal epithelial cells, and the balance between the two receptors is important for the outcome of tumor progression.…”

“…With respect to the presence of LT receptors in the intestine, the CysLT 1 receptor is expressed in intestinal epithelial cells and tumorderived intestinal cells [15] whereas the CysLT 2 receptor is expressed in differentiated intestinal epithelial cells but not in tumor-derived intestinal cell lines [18]. The BLT 1 receptor is also expressed in human colon cancer cell lines and colon cancer tissue but not in normal colon tissue [19].…”

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

“…Leukotriene B4 (LTB4), the final metabolite in the 5-LOX pathway, is able to enhance proliferation, increase survival and suppress the apoptosis of human cells. Blockade of the LTB4-signaling pathway induced apoptosis via the inhibition of ERK1/2 activation in colon cancer cells [20] . However, the mechanisms that 5-LOX/LTB4 promotes breast cancer cell growth remain unclear.…”

Arachidonate 5-Lipoxygenase Establishes Adaptive Humoral Immunity by Controlling Primary B Cells and Their Cognate T-Cell Help

“…Further investigations should elucidate the mechanism of the additive effects of Alox5 inhibitors as chemotherapeutic reagents to treat MCL. 48,49 In summary, we demonstrated the fundamental role of Alox5 in establishing specific antibody responses. Alox5 regulates not only primary resting B cells of the naive and memory B-cell phenotypes but also Tfh cell generation, thereby preserving specific antibody production.…”