Inhibition of 12‐LOX and COX‐2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K‐Akt signalling pathways

Abstract

Eicosanoids, the oxygenated metabolites of arachidonic acid (AA), mediate a variety of human diseases, such as cancer, inflammation and arthritis. To evaluate the role of eicosanoids in epidermoid carcinoma, the expression of AA metabolizing enzymes, such as lipoxygenases (LOXs) and cyclooxygenases (COXs), was analysed in a human epidermoid carcinoma cell line (A431). These studies revealed overexpression of 12-R-LOX and COX-2 in A431 cells. Baicalein (a 12-LOX inhibitor) and celecoxib (a COX-2 inhibitor) significantly reduced thymidine incorporation, whereas 12-(R)-HETE and 12-(S)-HETE (12-LOX metabolites) and PGE(2) (COX-2 metabolite) significantly enhanced thymidine incorporation, suggesting a role for these enzymes in the regulation of A431 cell proliferation. Further studies on the mechanism of cell death by baicalein and celecoxib revealed that the induction of apoptosis in A431 cells was associated with reduction in the Bcl-2/Bax ratio, release of cytochrome c, activation of caspase-3 and PARP cleavage. The apoptosis induced by baicalein and celecoxib was mediated by down regulation of ERK and PI3K-Akt pathways. Further, 12-(R)-HETE, 12-(S)-HETE and PGE(2) upregulated the p-ERK and p-Akt levels, suggesting the involvement of ERK and Akt pathways in the 12-LOX- and COX-2-mediated regulation of growth in A431 cells. Our findings suggest that 12-R-LOX and COX-2 play a critical role in the regulation of growth in epidermoid carcinoma and that their inhibitors may be of potential therapeutic importance.

The acid sphingomyelinase inhibitors block interferon-α-induced serotonin uptake via a COX-2/Akt/ERK/STAT-dependent pathway in T cells

“…Although several studies have reported that COX2 activation linked to activation of Akt and ERK is involved in cell growth or inflammation [38,39,49,50,63], little is known that the role of COX-2 activation associated with Akt/ERK pathway in an ability of 5-HT uptake. Celecoxib has no effect on the TNFα-induced activation of Akt and ERK to regulate inflammation in murine fibroblast cell line NIH-3T3 [63].…”

“…Several studies have reported that COX-2 inhibitor also lowers Akt activation, which mediates cell growth or inflammation [38,49,50]. However, little is known that the role of COX-2 induction linked to activation of Akt in an ability of 5-HT uptake.…”

Phospho‐ΔNp63α regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation

“…Arachidonate 12R-lipoxygenase (Alox12b) shown to be involved in mouse epidermal differentiation and skin barrier formation is induced in epidermoid carcinomas contributing to the tumor cell proliferation [18]. Genetic inactivation of Alox12b leads to thickening of the epidermis, hyper-proliferation of epidermal cells, and severe hyperkeratosis in mice [19], while the ALOX12B inhibition enhances human tumor cell death [20].…”

Arachidonic Acid Metabolism and Its Implication on Head and Neck Cancer

“…However, little is known about the molecular mechanism of the COX-2 pathway in the regulation of HNSCC cell growth. Molecular mechanism of cell apoptosis by COX-2/PGE 2 through phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been suggested in human epidermoid carcinoma cells (Agarwal et al, 2009).…”

“…LOX metabolites may enhance cancer cell survival through an increase in Bcl-2. In addition, they can upregulate the p-ERK and p-AKT levels, suggesting the involvement of ERK and AKT pathways in the LOX-mediated regulation of growth in cancer cells (Agarwal et al, 2009). However, it was found that metabolism of AA by 5-LOX activity promotes survival of cancer cells via signaling through PKCε, a pro-survival serine/threonine kinase which is not dependent on the AKT and ERK-pathway (Sarveswaran et al, 2011).…”