NF-κB-dependent Transcriptional Activation in Lung Carcinoma Cells by Farnesol Involves p65/RelA(Ser276) Phosphorylation via the MEK-MSK1 Signaling Pathway

Abstract

In this study, we demonstrate that treatment of human lung adenocarcinoma H460 cells with farnesol induces the expression of a number of immune response and inflammatory genes, including IL-6, CXCL3, IL-1␣, and COX-2. This response was dependent on the activation of the NF-B signaling pathway. Isoprenoids are intermediates of the cholesterol/sterol biosynthetic pathway and are formed from mevalonate, which is synthesized from acetyl-CoA by the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase, a major target for statins in the treatment of cardiovascular disease (1-3). Isoprenoids are important in the regulation of cell proliferation, apoptosis, and differentiation (4 -10).Farnesol and the related isoprenoids perillyl alcohol, geranylgeraniol, and geraniol have been reported to be effective in chemopreventative and -therapeutic strategies in several in vivo cancer models, including melanoma, colon, and pancreatic cancer (11)(12)(13)(14)(15)(16)(17)(18). In addition, these isoprenoids inhibit proliferation and induce cell death in a variety of neoplastic cell lines (5, 7, 10, 13, 15, 19 -21). The mechanisms by which these agents mediate their actions are not yet fully understood. In human pancreatic carcinoma cells, the antiproliferative response by these isoprenoids involves a p21-and p27-dependent mechanism (21). Farnesol has been reported to be able to weakly activate the farnesoid X-activated receptor (22) and inhibit phospholipase D (23), 3-hydroxy-3-methylglutaryl-CoA reductase activity (10), and the CDP-choline pathway (24). Study of farnesol-induced toxicity in yeast has indicated an important role for mitochondria and the PKC signaling pathway in the generation of reactive oxygen species (25).Recently, we reported that a large number of genes associated with the endoplasmic reticulum (ER) 2 stress response are rapidly induced by farnesol treatment, suggesting that farnesolinduced apoptosis is coupled to ER stress (26). Disturbance of ER homeostasis results in the activation of the unfolded protein response (27)(28)(29)(30). During this response, several prosurvival and proapoptotic signals are activated, and, depending on the extent of the ER stress, cells survive or undergo apoptosis. We demonstrated that farnesol induces activation of several MAPK pathways, including p38, MEK1/2-ERK1/2, and JNK1/2 (26) and provided evidence indicating that activation of MEK/ERK is an early and upstream event in farnesol-induced ER stress signaling cascade.In this study, we demonstrate that treatment of human lung adenocarcinoma H460 cells with farnesol induces the expression of a number of immune response and inflammatory-related genes, including COX-2 and several chemo/cytokines, and * This work was supported, in whole or in part, by the National Institutes of Health, NIEHS, Intramural Research Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely ...

Synergistic Induction of Inflammation by Bacterial Products Lipopolysaccharide and fMLP: An Important Microbial Pathogenic Mechanism

“…Previous studies identify serine 536 as the major phosphorylation site of p65 in response to LPS treatment (29,30), however, the phosphorylation of p65 at Ser 276 was also been reported by phosphotungstic acid and TNF (31,32). Joo and Jetten (33) showed that the S276A mutation significantly reduced the induction of NF-B transcription activation by farnesol, and that inhibition of MEK1/2 by U0126 or knockdown of MEK1/2 expression greatly diminished the phosphorylation of p65 at Ser276 site (but not that of Ser536), suggesting that phosphorylation of p65 at Ser276 is dependent on the activation of the MEK1/2-ERK1/2 pathway. Our unpublished data indicate that the fMLP stimulate a time-dependent increase in phosphorylation of ERK1/2 in human peripheral blood monocytes.…”

Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling

“…Phosphorylation at the same site can be achieved by multiple kinases, often in a cell-specific manner. For instance, Ser-276 of p65 is phosphorylated by protein kinase A (PKA) and MSK1, whereas phosphorylation at Ser-536 is mediated by different IB kinases (37,38). Phosphorylation of both Ser-536 and Ser-276 plays critical roles in regulating p65 activity (27, 36, 38 -41).…”

Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

“…S7C). These results suggest that PKA-Cβ1 directly phosphorylates p65, independently of activation of p38, ERK, or their downstream kinase MSK1 (mitogen-and stress-activated kinase 1) that has been shown to phosphorylate p65 (66)(67)(68). To further confirm whether PKA-Cβ directly phosphorylates p65, we performed in vitro kinase assay by using recombinant p65 and PKA-Cβ proteins.…”