Roles of the MEK1/2 and AKT pathways in CXCL12/CXCR4 induced cholangiocarcinoma cell invasion

Abstract

AIM:To evaluate the expression of C-X-C motif chemokine receptor 4 (CXCR4) and its signaling cascades, which were previously identified as a key factor for cancer cell progression and metastasis, in cholangiocarcinoma cell lines. METHODS:The expression of CXCR4 and its signaling cascades were determined in the cholangiocarcinoma cell lines (RMCCA1 and KKU100) by Western blotting. The invasion assays and the detection of actin polymerization were tested in these cholangiocarcinoma cells treated with CXC chemokine ligand -12 (CXCL12). RESULTS:Expression of CXCR4 was detected in both cholangiocarcinoma cell lines and activation of CXCR4 with CXCL12 triggered the signaling via the extracellular signal-regulated kinase-1/2 (ERK1/2) and phosphoinositide 3-kinase (PI3K) and induction of cholangiocarcinoma cell invasion, and displayed high levels of actin polymerization. Addition of CXCR4 inhibitor (AMD3100) abrogated CXCL12-induced phosphorylation of MEK1/2 and Akt in these cells. Moreover, treatment with MEK1/2 inhibitor (U0126) or PI3K inhibitor (LY294002) also attenuated the effect of CXCL12-induced cholangiocarcinoma cell invasion. CONCLUSION:These results indicated that the a c t i va t i o n o f C XC R 4 a n d i t s s i g n a l i n g p a t hway s (MEK1/2 and Akt) are essential for CXCL12-induced cholangiocarcinoma cell invasion. This rises Implications on a potential role for the inhibition of CXCR4 or its signal cascades in the treatment of cholangiocarcinoma.

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

“…Blocking CXCL12/CXCR4 interaction or inhibiting downstream intracellular signaling pathway may be useful for cancer therapy (4). We found that CXCL12 stimulation activated PI3K/Akt/mTOR signaling cascade in gastric cancer MKN-45 cells, which is consistent with the previous report, where phosphorylated Akt was utilized as an indirect marker for the activation of PI3K (7,(22)(23)(24)(25). By employing CHO-K1 cells stably expressing pEGFP-C1-Grp1-PH fusion protein, we demonstrated that CXCL12 stimulation resulted in generation of PtdIns(3,4,5)P 3 and the translocation of protein contained PH domain to cellular membrane, providing direct evidence that CXCL12 activated PI3K.…”

Basic fibroblast growth factor induces cholangiocarcinoma cell migration via activation of the MEK1/2 pathway

“…To the best of our knowledge, this is the first study to demonstrate the signal transduction pathways of bFGF/FGFR in cholangiocarcinoma cells. Previous studies also showed that activation of c-met, a hepatocyte growth factor receptor, or CXCR4 was capable of inducing cholangiocarcinoma cell migration via the activation of the MEK1/2 signaling pathway (20,21). Therefore, we suggest that MEK1/2 is the central signaling pathway for the control of cholangiocarcinoma cell migration.…”

Kaempferol inhibits the growth and metastasis of cholangiocarcinoma <italic>in vitro</italic> and <italic>in vivo</italic>

“…It is widely accepted that inactivating the PI3K/AKT pathway is one of the mechanisms through which kaempferol exerts its biochemical effects [17,40,41]. Furthermore, previous studies have reported that the PI3K/AKT pathway is a major survival pathway involved in the apoptosis and invasion of CCA [42,43]. Our data showed that kaempferol suppressed the expression levels of PI3K P110α, p-AKT, and p-p65, with no obvious changes in the total AKT protein level.…”