Alternative mammalian target of rapamycin (mTOR) signal activation in sorafenib-resistant hepatocellular carcinoma cells revealed by array-based pathway profiling

Mari Masuda, Wei Yu Chen, Akihiko Miyanaga, Yuka Nakamura, Kumiko Kawasaki, Tomohiro Sakuma, Masaya Ono, Chi Long Chen, Kazufumi Honda, Tesshi Yamada

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1429-1438
Number of pages10
JournalMolecular and Cellular Proteomics
Volume13
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Sirolimus
Hepatocellular Carcinoma
Chemical activation
Cells
Phosphotransferases
Ribosomal Protein S6
Phosphorylation
Biopsy
Biomarkers
Protein Array Analysis
Serine
Tumors
Exons
Genes
Fluorescence
sorafenib
Molecules
Databases
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry
  • Medicine(all)

Cite this

Alternative mammalian target of rapamycin (mTOR) signal activation in sorafenib-resistant hepatocellular carcinoma cells revealed by array-based pathway profiling. / Masuda, Mari; Chen, Wei Yu; Miyanaga, Akihiko; Nakamura, Yuka; Kawasaki, Kumiko; Sakuma, Tomohiro; Ono, Masaya; Chen, Chi Long; Honda, Kazufumi; Yamada, Tesshi.

In: Molecular and Cellular Proteomics, Vol. 13, No. 6, 2014, p. 1429-1438.

Research output: Contribution to journalArticle

Masuda, Mari ; Chen, Wei Yu ; Miyanaga, Akihiko ; Nakamura, Yuka ; Kawasaki, Kumiko ; Sakuma, Tomohiro ; Ono, Masaya ; Chen, Chi Long ; Honda, Kazufumi ; Yamada, Tesshi. / Alternative mammalian target of rapamycin (mTOR) signal activation in sorafenib-resistant hepatocellular carcinoma cells revealed by array-based pathway profiling. In: Molecular and Cellular Proteomics. 2014 ; Vol. 13, No. 6. pp. 1429-1438.
@article{de5b68f21509484cb51370d7cd2f792d,
title = "Alternative mammalian target of rapamycin (mTOR) signal activation in sorafenib-resistant hepatocellular carcinoma cells revealed by array-based pathway profiling",
abstract = "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.",
author = "Mari Masuda and Chen, {Wei Yu} and Akihiko Miyanaga and Yuka Nakamura and Kumiko Kawasaki and Tomohiro Sakuma and Masaya Ono and Chen, {Chi Long} and Kazufumi Honda and Tesshi Yamada",
year = "2014",
doi = "10.1074/mcp.M113.033845",
language = "English",
volume = "13",
pages = "1429--1438",
journal = "Molecular and Cellular Proteomics",
issn = "1535-9476",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Alternative mammalian target of rapamycin (mTOR) signal activation in sorafenib-resistant hepatocellular carcinoma cells revealed by array-based pathway profiling

AU - Masuda, Mari

AU - Chen, Wei Yu

AU - Miyanaga, Akihiko

AU - Nakamura, Yuka

AU - Kawasaki, Kumiko

AU - Sakuma, Tomohiro

AU - Ono, Masaya

AU - Chen, Chi Long

AU - Honda, Kazufumi

AU - Yamada, Tesshi

PY - 2014

Y1 - 2014

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84901919742&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901919742&partnerID=8YFLogxK

U2 - 10.1074/mcp.M113.033845

DO - 10.1074/mcp.M113.033845

M3 - Article

C2 - 24643969

AN - SCOPUS:84901919742

VL - 13

SP - 1429

EP - 1438

JO - Molecular and Cellular Proteomics

JF - Molecular and Cellular Proteomics

SN - 1535-9476

IS - 6

ER -