Tyr phosphatase-mediated P-ERK inhibition suppresses senescence in EIA + v-raf transformed cells, which, paradoxically, are apoptosis-protected in a MEK-dependent manner

Stefania de Vitis, Antonella Sonia Treglia, Luca Ulianich, Stefano Turco, Giuseppe Terrazzano, Angela Lombardi, Claudia Miele, Corrado Garbi, Francesco Beguinot, Bruno di Jeso

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13 Scopus citations

Abstract

Activation of the Ras-Raf-extracellular signal-regulated kinase (ERK) pathway causes not only proliferation and suppression of apoptosis but also the antioncogenic response of senescence. How these contrasting effects are reconciled to achieve cell transformation and cancer formation is poorly understood. In a systemof two-step carcinogenesis (dedifferentiated PC EIA, transformed PC EIA-polyoma-middle T [PC EIA + Py] and PC EIA-v-raf [PC EIA + raf] cells], v-raf cooperated with EIA by virtue of a strong prosurvival effect, not elicited by Py-middle T, evident toward serumdeprivation- and H2O9-induced apoptosis. Apoptosis was detected by DNA fragmentation and annexin V staining. The prosurvival function of v-raf was, in part,mitogen-activated protein kinase/ERK kinase (MEK)-dependent, as shown by pharmacological MEK inhibition. The MEK-dependent antiapoptotic effect of v-raf was exerted despite a lower level of P-ERK1/2 in EIA + raf cells with respect to EIA + Py/EIA cells, which was dependent on a high tyrosine phosphatase activity, as shown by orthovanadate blockade. An ERK1/2 tyrosine phosphatase was likely involved. The high tyrosine phosphatase activity was instrumental to the complete suppression of senescence, detected by β-galactosidase activity, because tyrosine phosphatase blockade induced senescence in EIA+raf but not in EIA+Py cells. High tyrosine phosphatase activity and evasion from senescence were confirmed in an anaplastic thyroid cancer cell line. Therefore, besides EIA, EIA + raf cells suppress senescence through a new mechanism, namely, phosphatase-mediated P-ERK1/2 inhibition, but, paradoxically, retain the oncogenic effects of the Raf-ERK pathway.We propose that the survival effect of Raf is not a function of absolute P-ERK1/2 levels at a given time but is rather dynamically dependent on greater variations after an apoptotic stimulus.

Original languageEnglish (US)
Pages (from-to)120-130
Number of pages11
JournalNeoplasia
Volume13
Issue number2
DOIs
Publication statusPublished - Feb 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Cancer Research

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