LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis.In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway.
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.
Two selected miRNAs, mir-204 and mir-320, were introduced into cholangiocarcinoma cell lines to examine their effects on potential target genes, Bcl-2 and Mcl-1, respectively.
We conclude that modulation of IL-6 mediated survival signaling pathways involving the p38 MAPK or downstream targets such as Mcl-1 may prove useful therapeutic strategies for human cholangiocarcinoma.
Immunohistochemistry showed that the serine/threonine kinase Akt and Mcl-1 are strongly expressed in the preneoplastic bile duct inflammatory disease primary sclerosing cholangitis and in human cholangiocarcinoma specimens.
Immunohistochemistry showed that the serine/threonine kinase Akt and Mcl-1 are strongly expressed in the preneoplastic bile duct inflammatory disease primary sclerosing cholangitis and in human cholangiocarcinoma specimens.
In conclusion, these studies not only demonstrate that Mcl-1 mediates TRAIL resistance in cholangiocarcinoma cells by blocking the mitochondrial pathway of cell death but also identify two strategies for circumventing this resistance.