Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\26901106
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Hepatology
2016 ; 63
(3
): 813-26
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding
proteins in hepatocellular carcinoma cells
#MMPMID26901106
Samarin J
; Laketa V
; Malz M
; Roessler S
; Stein I
; Horwitz E
; Singer S
; Dimou E
; Cigliano A
; Bissinger M
; Falk CS
; Chen X
; Dooley S
; Pikarsky E
; Calvisi DF
; Schultz C
; Schirmacher P
; Breuhahn K
Hepatology
2016[Mar]; 63
(3
): 813-26
PMID26901106
show ga
Transcription factors of the far-upstream element-binding protein (FBP) family
represent cellular pathway hubs, and their overexpression in liver cancer
(hepatocellular carcinoma [HCC]) stimulates tumor cell proliferation and
correlates with poor prognosis. Here we determine the mode of oncogenic FBP
overexpression in HCC cells. Using perturbation approaches (kinase inhibitors,
small interfering RNAs) and a novel system for rapalog-dependent activation of
AKT isoforms, we demonstrate that activity of the
phosphatidylinositol-4,5-biphosphate 3-kinase/AKT pathway is involved in the
enrichment of nuclear FBP1 and FBP2 in liver cancer cells. In human HCC tissues,
phospho-AKT significantly correlates with nuclear FBP1/2 accumulation and
expression of the proliferation marker KI67. Mechanistic target of rapamycin
(mTOR) inhibition or blockade of its downstream effector eukaryotic translation
initiation factor 4E activity equally reduced FBP1/2 concentrations. The mTORC1
inhibitor rapamycin diminishes FBP enrichment in liver tumors after hydrodynamic
gene delivery of AKT plasmids. In addition, the multikinase inhibitor sorafenib
significantly reduces FBP levels in HCC cells and in multidrug resistance
2-deficient mice that develop HCC due to severe inflammation. Both FBP1/2
messenger RNAs are highly stable, with FBP2 being more stable than FBP1.
Importantly, inhibition of phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR
signaling significantly diminishes FBP1/2 protein stability in a
caspase-3/-7-dependent manner. CONCLUSION: These data provide insight into a
transcription-independent mechanism of FBP protein enrichment in liver cancer;
further studies will have to show whether this previously unknown interaction
between phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR pathway activity
and caspase-mediated FBP stabilization allows the establishment of interventional
strategies in FBP-positive HCCs.