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.

The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms / Ludovica, Ciuffreda; C., Di Sanza; Ursula Cesta, Incani; Adriana, Eramo; Marianna, Desideri; Francesca, Biagioni; Daniela, Passeri; Italia, Falcone; Giovanni, Sette; Paola, Bergamo; Andrea, Anichini; Kanaga, Sabapathy; James A., Mccubrey; Ricciardi, Maria Rosaria; Tafuri, Agostino; Giovanni, Blandino; Augusto, Orlandi; R., De Maria; Francesco, Cognetti; D., Del Bufalo; Michele, Milella. - In: JOURNAL OF MOLECULAR MEDICINE. - ISSN 0946-2716. - STAMPA. - 90:6(2012), pp. 667-679. [10.1007/s00109-011-0844-1]

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

RICCIARDI, Maria Rosaria;TAFURI, Agostino;Francesco Cognetti;
2012

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
c-jun; crosstalk; mapk; mir-25; pi3k; pten
01 Pubblicazione su rivista::01a Articolo in rivista
The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms / Ludovica, Ciuffreda; C., Di Sanza; Ursula Cesta, Incani; Adriana, Eramo; Marianna, Desideri; Francesca, Biagioni; Daniela, Passeri; Italia, Falcone; Giovanni, Sette; Paola, Bergamo; Andrea, Anichini; Kanaga, Sabapathy; James A., Mccubrey; Ricciardi, Maria Rosaria; Tafuri, Agostino; Giovanni, Blandino; Augusto, Orlandi; R., De Maria; Francesco, Cognetti; D., Del Bufalo; Michele, Milella. - In: JOURNAL OF MOLECULAR MEDICINE. - ISSN 0946-2716. - STAMPA. - 90:6(2012), pp. 667-679. [10.1007/s00109-011-0844-1]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/434036
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