Secreted PLA2 induces proliferation in astrocytoma through the EGF receptor: another inflammation-cancer link
10 páginas, 5 figuras. ; We have investigated mechanisms that contribute to reinforce the relationship between inflammation and cancer. Secreted phospholipase A2 group IIA (sPLA2-IIA) is a molecule relevant in inflammatory events and has been proposed as a marker for some of these. Previously, we reported the mitogenic properties of this sPLA2 in the human astrocytoma cell line 1321N1. Here, we go deeper into the mechanisms that link this inflammatory protein with proliferation in one of the most aggressive types of tumors. We found that phosphorylation of the extracellular regulated kinase (ERK) was preceded by the activation of the small GTPase Ras, and both failed to be activated by inhibiting protein kinase C (PKC). Fractionation and immunofluorescence studies revealed translocation of PKC alpha, delta, and epsilon to the membrane fraction upon stimulation with sPLA2-IIA. Immunoprecipitation analysis showed that sPLA2-IIA induces phosphorylation of the epidermal growth factor receptor (EGFR) through a PKC-dependent pathway. We found that phosphorylation of this receptor contributed to Ras and ERK activation and that inhibition of ERK, PKC, and EGFR blocked the mitogenic response induced by sPLA2-IIA. This study showed that sPLA2-IIA is able to bring into play EGFR to trigger its signaling and that PKC leads the distribution of resources. Interestingly, we found that this is not a cell-specific response, because sPLA2-IIA was also able to transactivate EGFR in MCF7 human breast cancer cells. Therefore, this mechanism could contribute to worsen the prognosis of a tumor in an inflammatory microenvironment. We also present more links of the tumor chain possibly susceptible to targeting. ; This work was supported by the Ramón y Cajal Program (to M.H.), F.P.I. Program from the Autonomous Government of Castilla y León. (to R.M.), both cofunded by F.S.E and by the ISCIII, Red de Centros RECAVA, C03/01 (to P.M.H. and M.D.G.C.), and by grants SAF2005-01242 and SAF2009-08407 from the Spanish Ministry of Science and Innovation, and CSI11A08 from the Autonomous Government of Castilla y León. ; Peer reviewed
