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Journal of Molecular Medicine

, Volume 90, Issue 6, pp 667–679 | Cite as

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

  • Ludovica Ciuffreda
  • Cristina 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
  • Maria Rosaria Ricciardi
  • Agostino Tafuri
  • Giovanni Blandino
  • Augusto Orlandi
  • Ruggero De Maria
  • Francesco Cognetti
  • Donatella Del Bufalo
  • Michele MilellaEmail author
Original Article

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.

Keywords

MAPK PI3K PTEN Crosstalk c-Jun miR-25 

Notes

Acknowledgments

This work was supported in part by grants from the Italian Association for Cancer Research (AIRC), the Cariplo Foundation, and the Italian Ministry of Health.

Supplementary material

109_2011_844_MOESM1_ESM.pdf (201 kb)
ESM 1 PDF 123 kb

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ludovica Ciuffreda
    • 1
  • Cristina Di Sanza
    • 1
  • Ursula Cesta Incani
    • 1
  • Adriana Eramo
    • 2
  • Marianna Desideri
    • 1
  • Francesca Biagioni
    • 1
  • Daniela Passeri
    • 3
  • Italia Falcone
    • 1
  • Giovanni Sette
    • 2
  • Paola Bergamo
    • 1
  • Andrea Anichini
    • 4
  • Kanaga Sabapathy
    • 5
  • James A. McCubrey
    • 6
  • Maria Rosaria Ricciardi
    • 7
  • Agostino Tafuri
    • 7
  • Giovanni Blandino
    • 1
  • Augusto Orlandi
    • 3
  • Ruggero De Maria
    • 2
  • Francesco Cognetti
    • 1
  • Donatella Del Bufalo
    • 1
  • Michele Milella
    • 1
    Email author
  1. 1.Division of Medical Oncology A, the Laboratory of Experimental Preclinical Chemotherapy and Translational OncogenomicsRegina Elena National Cancer InstituteRomeItaly
  2. 2.Department of Hematology, Oncology, and Molecular MedicineIstituto Superiore di SanitàRomeItaly
  3. 3.Anatomic PathologyTor Vergata University of RomeRomeItaly
  4. 4.Human Tumor Immunobiology UnitFondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei TumoriMilanItaly
  5. 5.Laboratory of Molecular CarcinogenesisNational Cancer CentreSingaporeSingapore
  6. 6.Department of Microbiology and Immunology, Brody School of MedicineEast Carolina UniversityGreenvilleUSA
  7. 7.Department of Cellular Biotechnologies and HematologyUniversity of Rome ‘La Sapienza’RomeItaly

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