PTEN/MAPK pathways play a key role in platelet‐activating factor‐induced experimental pulmonary tumor metastasis

Kim, Han-A; Kim, Kyoung-Jin; Seo, Kook Heon; Lee, Hern-Ku; Im, Suhn-Young

doi:10.1016/j.febslet.2012.10.034

“…PAF induces diverse cellular effects through its specific receptor, PAFR, which belongs to the G-protein coupled receptor (GPCR) family and transduces cell signals via G-proteins and associated protein phosphorylation cascades [ 5 - 7 ]. Many types of cells, when challenged with PAF, showed the activation of tyrosine kinase [ 8 ] and protein phosphorylation [ 9 - 11 ].…”

Section: Introductionmentioning

confidence: 99%

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Yu

¹

,

Zhang

²

,

Zhang

³

et al. 2014

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundWe previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer.MethodsExpression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay.ResultsOur data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner.ConclusionsThe results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.

show abstract

“…PAF induces diverse cellular effects through its specific receptor, PAFR, which belongs to the G-protein coupled receptor (GPCR) family and transduces cell signals via G-proteins and associated protein phosphorylation cascades [5][6][7]. Many types of cells, when challenged with PAF, showed the activation of tyrosine kinase [8] and protein phosphorylation [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Yu

¹

,

Zhang

²

,

Zhang

³

et al. 2014

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundWe previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer.MethodsExpression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay.ResultsOur data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner.ConclusionsThe results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.

show abstract

“…5 Platelet activating factor (PAF), a potent phospholipid, promotes lung cancer growth and metastasis. 6 PAF is hydrolyzed by phospholipase A2 to produce lysophospholipid PAFs (lysoPAFs). Patients with lung cancer have increased expression and activity of phospholipase A2.…”

mentioning

confidence: 99%