PMID- 22215152
OWN - NLM
STAT- MEDLINE
DCOM- 20121002
LR  - 20211021
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 90
IP  - 6
DP  - 2012 Jun
TI  - The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and 
      tensin homolog (PTEN) expression through multiple mechanisms.
PG  - 667-79
LID - 10.1007/s00109-011-0844-1 [doi]
AB  - 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.
FAU - Ciuffreda, Ludovica
AU  - Ciuffreda L
AD  - Division of Medical Oncology A, Laboratory of Experimental Preclinical 
      Chemotherapy and Translational Oncogenomics, Regina Elena National Cancer 
      Institute, Chianesi, n. 53, 00144, Rome, Italy.
FAU - Di Sanza, Cristina
AU  - Di Sanza C
FAU - Cesta Incani, Ursula
AU  - Cesta Incani U
FAU - Eramo, Adriana
AU  - Eramo A
FAU - Desideri, Marianna
AU  - Desideri M
FAU - Biagioni, Francesca
AU  - Biagioni F
FAU - Passeri, Daniela
AU  - Passeri D
FAU - Falcone, Italia
AU  - Falcone I
FAU - Sette, Giovanni
AU  - Sette G
FAU - Bergamo, Paola
AU  - Bergamo P
FAU - Anichini, Andrea
AU  - Anichini A
FAU - Sabapathy, Kanaga
AU  - Sabapathy K
FAU - McCubrey, James A
AU  - McCubrey JA
FAU - Ricciardi, Maria Rosaria
AU  - Ricciardi MR
FAU - Tafuri, Agostino
AU  - Tafuri A
FAU - Blandino, Giovanni
AU  - Blandino G
FAU - Orlandi, Augusto
AU  - Orlandi A
FAU - De Maria, Ruggero
AU  - De Maria R
FAU - Cognetti, Francesco
AU  - Cognetti F
FAU - Del Bufalo, Donatella
AU  - Del Bufalo D
FAU - Milella, Michele
AU  - Milella M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120104
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Benzamides)
RN  - 0 (Enzyme Inhibitors)
RN  - 86K0J5AK6M (mirdametinib)
RN  - 9N3CBB0BIQ (Diphenylamine)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
SB  - IM
MH  - Animals
MH  - Benzamides/pharmacology
MH  - Diphenylamine/analogs & derivatives/pharmacology
MH  - Disease Models, Animal
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - *Gene Expression Regulation, Enzymologic/drug effects
MH  - Melanoma/enzymology
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - PTEN Phosphohydrolase/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Signal Transduction
EDAT- 2012/01/05 06:00
MHDA- 2012/10/04 06:00
CRDT- 2012/01/05 06:00
PHST- 2011/09/20 00:00 [received]
PHST- 2011/11/17 00:00 [accepted]
PHST- 2011/11/16 00:00 [revised]
PHST- 2012/01/05 06:00 [entrez]
PHST- 2012/01/05 06:00 [pubmed]
PHST- 2012/10/04 06:00 [medline]
AID - 10.1007/s00109-011-0844-1 [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2012 Jun;90(6):667-79. doi: 10.1007/s00109-011-0844-1. Epub 
      2012 Jan 4.