The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms

Ruggero De Maria Marchiano, Giovanni Sette, Ludovica Ciuffreda, Cristina Di Sanza, Ursula Cesta Incani, Adriana Eramo, Marianna Desideri, Francesca Biagioni, Daniela Passeri, Italia Falcone, Paola Bergamo, Andrea Anichini, Kanaga Sabapathy, James A. Mccubrey, Maria Rosaria Ricciardi, Agostino Tafuri, Giovanni Blandino, Augusto Orlandi, Francesco Cognetti, Donatella Del BufaloMichele Milella

Risultato della ricerca: Contributo in rivistaArticolo in rivista

51 Citazioni (Scopus)

Abstract

The mitogen-activated protein kinase (MAPK) and PI3K pathways are regulated by extensive crosstalk, occurring at different levels. In tumors, transactivation of the alternate pathway is a frequent "escape" mechanism, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity. Here we show that, in the M14 melanoma model, simultaneous inhibition of both MEK and mammalian target of rapamycin (mTOR) achieves synergistic effects at suboptimal concentrations, but becomes frankly antagonistic in the presence of relatively high concentrations of MEK inhibitors. This observation led to the identification of a novel crosstalk mechanism, by which either pharmacologic or genetic inhibition of constitutive MEK signaling restores phosphatase and tensin homolog (PTEN) expression, both in vitro and in vivo, and inhibits downstream signaling through AKT and mTOR, thus bypassing the need for double pathway blockade. This appears to be a general regulatory mechanism and is mediated by multiple mechanisms, such as MAPK-dependent c-Jun and miR-25 regulation. Finally, PTEN upregulation appears to be a major effector of MEK inhibitors' antitumor activity, as cancer cells in which PTEN is inactivated are consistently more resistant to the growth inhibitory and anti-angiogenic effects of MEK blockade. © 2012 Springer-Verlag.
Lingua originaleEnglish
pagine (da-a)667-679
Numero di pagine13
RivistaJournal of Molecular Medicine
Volume90
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Animals
  • Benzamides
  • Crosstalk
  • Diphenylamine
  • Disease Models, Animal
  • Drug Discovery3003 Pharmaceutical Science
  • Enzyme Activation
  • Enzyme Inhibitors
  • Gene Expression Regulation, Enzymologic
  • Genetics (clinical)
  • MAPK
  • Melanoma
  • Mice
  • Mitogen-Activated Protein Kinases
  • Molecular Medicine
  • PI3K
  • PTEN
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases
  • Signal Transduction
  • c-Jun
  • miR-25

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