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


CONCLUSIONS
These results indicated that the activation of CXCR4 and its signaling pathways (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.
Leelawat
Kawin
K
Department of Surgery, Rajavithi Hospital, Bangkok 10400, Thailand. sckll@mahidol.ac.th
Leelawat
Surang
S
Narong
Siriluck
S
Hongeng
Suradej
S
D001596:Benzylamines; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D001653:Bile Ducts, Intrahepatic; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000502:physiology*; D018281:Cholangiocarcinoma / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002867:Chromones / Q000494:pharmacology; D000080027:Cyclams; D003599:Cytoskeleton / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D001596:Benzylamines; D002070:Butadienes; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002867:Chromones; D000080027:Cyclams; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D009025:Morpholines; D009570:Nitriles; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C088327:plerixafor