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Cytosolic Phospholipase A₂ Regulates Cell Growth in RET/PTC-Transformed Thyroid Cells

¹ Department of Cell Biology and Oncology and ² Environmental Sciences Center, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy and ³ Istituto di Endocrinologia ed Oncologia Sperimentale del CNR "G. Salvatore," c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, University "Federico II," Naples, Italy

Requests for reprints: Stefania Mariggiò or Daniela Corda, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Via Nazionale 8/A, 66030 Santa Maria Imbaro (Chieti), Italy. Phone: 39-0872-570338; Fax: 39-0872-570412; E-mail: mariggio{at}negrisud.it or corda{at}negrisud.it.

Modulation of cytosolic phospholipase A₂ (PLA₂) expression levels and production of its metabolites have been reported in several tumor types, indicating involvement of arachidonic acid and its derivatives in tumorigenesis. Following our demonstration that the PLA₂ group IV isoform (PLA₂IV) controls TSH-independent growth of normal thyroid (PCCl₃) cells, we have investigated the mitogenic role of PLA₂IV in rat thyroid cells transformed by the RET/PTC oncogenes (PC-PTC cells). We now report that PLA₂IV acts downstream of the RET/PTC oncogenes in a novel pathway controlling RET-dependent cell proliferation. In addition, we show that PLA₂IV is in its phosphorylated/active form not only in RET/PTC-transformed cells and in cells derived from human papillary carcinomas but also in lysates from tumor tissues, thus relating constitutive activation of PLA₂IV to RET/PTC-dependent tumorigenesis. Moreover, p38 stress-activated protein kinase is the downstream effector of RET/PTC that is responsible for PLA₂IV phosphorylation and activity. In summary, our data elucidate a novel mechanism in the control of thyroid tumor cell growth that is induced by the RET/PTC oncogenes and which is distinguishable from that of other oncogenes, such as BRAF. This mechanism is mediated by PLA₂IV and should be amenable to targeted pharmacologic intervention. [Cancer Res 2007;67(24):11769–78]

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