PMID- 24643969
OWN - NLM
STAT- MEDLINE
DCOM- 20150219
LR  - 20211203
IS  - 1535-9484 (Electronic)
IS  - 1535-9476 (Print)
IS  - 1535-9476 (Linking)
VI  - 13
IP  - 6
DP  - 2014 Jun
TI  - Alternative mammalian target of rapamycin (mTOR) signal activation in 
      sorafenib-resistant hepatocellular carcinoma cells revealed by array-based 
      pathway profiling.
PG  - 1429-38
LID - 10.1074/mcp.M113.033845 [doi]
AB  - Sorafenib is a multi-kinase inhibitor that has been proven effective for the 
      treatment of unresectable hepatocellular carcinoma (HCC). However, its precise 
      mechanisms of action and resistance have not been well established. We have 
      developed high-density fluorescence reverse-phase protein arrays and used them to 
      determine the status of 180 phosphorylation sites of signaling molecules in the 
      120 pathways registered in the NCI-Nature curated database in 23 HCC cell lines. 
      Among the 180 signaling nodes, we found that the level of ribosomal protein S6 
      phosphorylated at serine residue 235/236 (p-RPS6 S235/236) was most significantly 
      correlated with the resistance of HCC cells to sorafenib. The high expression of 
      p-RPS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained 
      from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC 
      cells showed constitutive activation of the mammalian target of rapamycin (mTOR) 
      pathway, but whole-exon sequencing of kinase genes revealed no evident alteration 
      in the pathway. p-RPS6 S235/236 is a potential biomarker that predicts 
      unresponsiveness of HCC to sorafenib. The use of mTOR inhibitors may be 
      considered for the treatment of such tumors.
CI  - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Masuda, Mari
AU  - Masuda M
AD  - From the double daggerDivision of Chemotherapy and Clinical Research, National Cancer Center 
      Research Institute, Tokyo, 104-0045 Japan; mamasuda@ncc.go.jp.
FAU - Chen, Wei-Yu
AU  - Chen WY
AD  -  paragraph signDepartment of Pathology, Wan Fan Hospital and Taipei Medical University, Taipei, 
      11031 Taiwan;
FAU - Miyanaga, Akihiko
AU  - Miyanaga A
AD  - From the double daggerDivision of Chemotherapy and Clinical Research, National Cancer Center 
      Research Institute, Tokyo, 104-0045 Japan;
FAU - Nakamura, Yuka
AU  - Nakamura Y
AD  - From the double daggerDivision of Chemotherapy and Clinical Research, National Cancer Center 
      Research Institute, Tokyo, 104-0045 Japan;
FAU - Kawasaki, Kumiko
AU  - Kawasaki K
AD  -  ||BioBusiness Group, Mitsui Knowledge Industry, Tokyo, 164-8555 Japan.
FAU - Sakuma, Tomohiro
AU  - Sakuma T
AD  -  ||BioBusiness Group, Mitsui Knowledge Industry, Tokyo, 164-8555 Japan.
FAU - Ono, Masaya
AU  - Ono M
AD  - From the double daggerDivision of Chemotherapy and Clinical Research, National Cancer Center 
      Research Institute, Tokyo, 104-0045 Japan;
FAU - Chen, Chi-Long
AU  - Chen CL
AD  -  paragraph signDepartment of Pathology, Wan Fan Hospital and Taipei Medical University, Taipei, 
      11031 Taiwan;
FAU - Honda, Kazufumi
AU  - Honda K
AD  - From the double daggerDivision of Chemotherapy and Clinical Research, National Cancer Center 
      Research Institute, Tokyo, 104-0045 Japan;
FAU - Yamada, Tesshi
AU  - Yamada T
AD  - From the double daggerDivision of Chemotherapy and Clinical Research, National Cancer Center 
      Research Institute, Tokyo, 104-0045 Japan;
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140318
PL  - United States
TA  - Mol Cell Proteomics
JT  - Molecular & cellular proteomics : MCP
JID - 101125647
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phenylurea Compounds)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
EIN - Mol Cell Proteomics. 2020 Jan;19(1):223. PMID: 31894100
MH  - Carcinoma, Hepatocellular/drug therapy/*genetics/pathology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Gene Expression Regulation, Neoplastic/drug effects/genetics
MH  - Humans
MH  - Liver Neoplasms/drug therapy/*genetics/pathology
MH  - Neoplasm Proteins/biosynthesis
MH  - Niacinamide/analogs & derivatives/therapeutic use
MH  - Phenylurea Compounds/therapeutic use
MH  - Phosphorylation
MH  - Proteomics
MH  - Signal Transduction/drug effects/immunology
MH  - Sorafenib
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*biosynthesis/metabolism
PMC - PMC4047464
EDAT- 2014/03/20 06:00
MHDA- 2015/02/20 06:00
PMCR- 2015/06/01
CRDT- 2014/03/20 06:00
PHST- 2014/03/20 06:00 [entrez]
PHST- 2014/03/20 06:00 [pubmed]
PHST- 2015/02/20 06:00 [medline]
PHST- 2015/06/01 00:00 [pmc-release]
AID - S1535-9476(20)33075-9 [pii]
AID - M113.033845 [pii]
AID - 10.1074/mcp.M113.033845 [doi]
PST - ppublish
SO  - Mol Cell Proteomics. 2014 Jun;13(6):1429-38. doi: 10.1074/mcp.M113.033845. Epub 
      2014 Mar 18.