FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling.

[cholangiocarcinoma]

Interleukin 6 (IL -6 )-mediated signal transducers and activators of transcription 3 (STAT-3 ) phosphorylation (activation ) is aberrantly sustained in cholangiocarcinoma cells resulting in enhanced myeloid cell leukemia 1 (Mcl-1 ) expression and resistance to apoptosis . FTY 720 , a new immunosuppressant , derived from ISP-1 , has been studied for its putative anti-cancer properties . This study aimed to elucidate the mechanism by which FTY 720 mediates antitumor effects in cholangiocarcinoma (CC ) cells .Three CC cell lines were examined , QBC 939 , TFK-1 , and HuCCT 1 . The therapeutic effects of FTY 720 were evaluated in vitro and in vivo . Cell proliferation , apoptosis , cell cycle , invasive potential , and epithelial- mesenchy-mal transition (EMT ) were examined .FTY 720 greatly inhibited CC cells proliferation and EMT in vitro and in vivo , and this effect was associated with dephosphorylation of STAT 3 tyr 705 . FTY 720 induced apoptosis and G 1 phase arrest in CC cells , and inhibited invasion of CC cells . Western blot analysis showed that FTY 720 induced cleavage of caspases 3 , 8 and 9 , and of PARP , in a dose-dependent manner , consistent with a substantial decrease in p -STAT 3 , Bcl-x L , Bcl-2 , survivin , cyclin D 1 , cyclin E , N-cadherin , vimentin , VEGF and TWIST 1 . In vivo studies showed that tumor growth and metastasis were significantly suppressed after FTY 720 treatment .These results suggest that FTY 720 induces a significant decrease in p -STAT 3 , which inhibits proliferation and EMT of CC cells , and then induces G 1 phase arrest and apoptosis . We have characterized a novel immunosuppressant , which shows potential anti-tumor effects on CC via p -STAT 3 inhibition . FTY 720 merits further investigation and warrants clinical evaluation .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated