RRC ID 52513
Author Yokoi K, Kobayashi A, Motoyama H, Kitazawa M, Shimizu A, Notake T, Yokoyama T, Matsumura T, Takeoka M, Miyagawa SI.
Title Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib.
Journal Oncol. Rep.
Abstract Cholangiocarcinoma (CCC) is a strongly aggressive malignancy for which surgical resection is the only potential curative therapy. Sorafenib, a multikinase inhibitor of the RAF/MEK/ERK pathway, is a molecular-targeted drug that is approved for hepatocellular carcinoma (HCC) but not for CCC. The differences in signaling pathway characteristics under sorafenib treatment between HCC (HLF, Huh7, PLC/PRF/5) and CCC (RBE, YSCCC, Huh28) cell lines were therefore investigated using cell proliferation, western blotting, and apoptosis analyses. Sorafenib inhibited cell growth significantly less in CCC cells than in HCC cells, with lower suppression of ERK phosphorylation. Significantly decreased AKT Ser473 phosphorylation in HCC cells, and conversely enhanced phosphorylation of AKT Ser473 and mTORC2 in CCC cells, were observed with sorafenib treatment. Disassembly of the mTORC2 complex in RBE cells with siRNA targeting Rictor resulted in the downregulation of AKT Ser473 phosphorylation and enhanced apoptosis presumably via increased FOXO1, which consequently suppressed RBE cell proliferation. Phosphorylation of mTORC1 and autophagy were not influenced by sorafenib in CCC cells. Simultaneous administration of everolimus to suppress activated mTORC1 in RBE cells revealed that combined everolimus and sorafenib treatment under mTORC2 disassembly could enhance growth inhibition through the suppression of both sorafenib- and everolimus-dependent AKT Ser473 phosphorylation in addition to the inhibition of mTORC1 phosphorylation. Prevention of escape by AKT/mTOR signaling from the RAF/MEK/ERK pathway in sorafenib treatment by suppressing mTORC2 activity may lead to promising new approaches in CCC therapy.
Volume 39(2)
Pages 843-850
Published 2018-2
DOI 10.3892/or.2017.6153
PMID 29251327
MeSH Bile Duct Neoplasms / drug therapy Bile Duct Neoplasms / metabolism* Cell Line, Tumor Cell Proliferation / drug effects Cell Survival Cholangiocarcinoma / drug therapy Cholangiocarcinoma / metabolism* Drug Resistance, Neoplasm* Drug Synergism Everolimus / pharmacology Forkhead Box Protein O1 / metabolism Gene Expression Regulation, Neoplastic Humans MAP Kinase Signaling System / drug effects Niacinamide / analogs & derivatives* Niacinamide / pharmacology Phenylurea Compounds / pharmacology* Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-akt / metabolism Signal Transduction / drug effects* Sorafenib TOR Serine-Threonine Kinases / metabolism
IF 3.041
Human and Animal Cells RBE(RCB1292) YSCCC(RCB1549)