Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26497676
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-?1-induced
growth inhibition by targeting Smad3 linker region
#MMPMID26497676
Jeon WK
; Choi J
; Park SJ
; Jo EJ
; Lee YK
; Lim S
; Kim JH
; Letterio JJ
; Liu F
; Kim SJ
; Kim BC
Oncotarget
2015[Dec]; 6
(39
): 41650-66
PMID26497676
show ga
Leukotriene B4 (LTB4) is a potent pro-inflammatory eicosanoid that is derived
from arachidonic acid, and its signaling is known to have a tumor-promoting role
in several cancer types. In this study, we investigated whether enhanced LTB4
signaling confers resistance to the cytostatic transforming growth factor-?1
(TGF-?1) response. We found that LTB4 pretreatment or ectopic expression of BLT1,
a high affinity LTB4 receptor, fully abrogated TGF-?1-induced cell cycle arrest
and expression of p15INK4B and p27KIP1. Mechanism study revealed that
LTB4-mediated suppression of TGF-?1-induced Smad3 activation and growth
inhibition was due to enhanced phosphorylation of Smad3 linker region (pSmad3L)
through activation of BLT1-NAD(P)H oxidase (NOX)-reactive oxygen species
(ROS)-epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase
(PI3-K)-extracellular signal-activated kinase1/2 (ERK1/2)-linked signaling
cascade. Furthermore, the LTB4/BLT1 signaling pathway leading to pSmad3L was
constitutively activated in breast cancer cells and was correlated with
TGF-?1-resistant growth of the cells in vitro and in vivo. In human breast cancer
tissues, the expression level of pSmad3L (Thr179) had a positive correlation with
BLT1 expression. Collectively, our data demonstrate for the first time that the
induction of pSmad3L through BLT1-NOX-ROS-EGFR-PI3K-ERK1/2 signaling pathway is a
key mechanism by which LTB4 blocks the anti-proliferative responses of TGF-?1,
providing a novel mechanistic insight into the connection between enhanced
inflammatory signal and cancer cell growth.
free
free
free
