Secreted PLA2 induces proliferation in astrocytoma through the EGF receptor: another inflammation-cancer link.
We have investigated mechanisms that contribute to reinforce the relationship between inflammation and cancer. Secreted phospholipase A(2) group IIA (sPLA(2)-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 sPLA(2) 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 sPLA(2)-IIA. Immunoprecipitation analysis showed that sPLA(2)-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 sPLA(2)-IIA. This study showed that sPLA(2)-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 sPLA(2)-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.
Hernández
Marita
M
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, C/Sanz y Forés s/n, 47003 Valladolid, Spain. maritahg@ibgm.uva.es
Martín
Rubén
R
García-Cubillas
Miriam Daniela
MD
Maeso-Hernández
Patricia
P
Nieto
María Luisa
ML
D001254:Astrocytoma / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation
C512478:EGFR protein, human; D066246:ErbB Receptors; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human