PMID- 24312415
OWN - NLM
STAT- MEDLINE
DCOM- 20140805
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 11
DP  - 2013
TI  - Branched chain amino acid suppresses hepatocellular cancer stem cells through the 
      activation of mammalian target of rapamycin.
PG  - e82346
LID - 10.1371/journal.pone.0082346 [doi]
LID - e82346
AB  - Differentiation of cancer stem cells (CSCs) into cancer cells causes increased 
      sensitivity to chemotherapeutic agents. Although inhibition of mammalian target 
      of rapamycin (mTOR) leads to CSC survival, the effect of branched chain amino 
      acids (BCAAs), an mTOR complex 1 (mTORC1) activator remains unknown. In this 
      study, we examined the effects of BCAA on hepatocellular carcinoma (HCC) cells 
      expressing a hepatic CSC marker, EpCAM. We examined the effects of BCAA and/or 
      5-fluorouracil (FU) on expression of EpCAM and other CSC-related markers, as well 
      as cell proliferation in HCC cells and in a xenograft mouse model. We also 
      characterized CSC-related and mTOR signal-related molecule expression and 
      tumorigenicity in HCC cells with knockdown of Rictor or Raptor, or overexpression 
      of constitutively active rheb (caRheb). mTOR signal-related molecule expression 
      was also examined in BCAA-treated HCC cells. In-vitro BCAA reduced the frequency 
      of EpCAM-positive cells and improved sensitivity to the anti-proliferative effect 
      of 5-FU. Combined 5-FU and BCAA provided better antitumor efficacy than 5-FU 
      alone in the xenograft model. Stimulation with high doses of BCAA activated 
      mTORC1. Knockdown and overexpression experiments revealed that inhibition of mTOR 
      complex 2 (mTORC2) or activation of mTORC1 led to decreased EpCAM expression and 
      little or no tumorigenicity. BCAA may enhance the sensitivity to chemotherapy by 
      reducing the population of cscs via the mTOR pathway. This result suggests the 
      utility of BCAA in liver cancer therapy.
FAU - Nishitani, Shinobu
AU  - Nishitani S
AD  - Exploratory Research Laboratories, Research Center, Ajinomoto Pharmaceuticals, 
      Co, Ltd, Kanagawa, Japan.
FAU - Horie, Mayumi
AU  - Horie M
FAU - Ishizaki, Sonoko
AU  - Ishizaki S
FAU - Yano, Hirohisa
AU  - Yano H
LA  - eng
PT  - Journal Article
DEP - 20131127
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amino Acids, Branched-Chain)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (DNA Primers)
RN  - 0 (EPCAM protein, human)
RN  - 0 (Epithelial Cell Adhesion Molecule)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acids, Branched-Chain/*physiology
MH  - Antigens, Neoplasm/metabolism
MH  - Apoptosis
MH  - Base Sequence
MH  - Carcinoma, Hepatocellular/*metabolism/pathology
MH  - Cell Adhesion Molecules/metabolism
MH  - Cell Line, Tumor
MH  - DNA Primers
MH  - Epithelial Cell Adhesion Molecule
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Liver Neoplasms/*metabolism/pathology
MH  - Neoplastic Stem Cells/cytology/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC3842306
COIS- Competing Interests: This research belongs to Ajinomoto Pharmaceutical Company. 
      The authors declare that they have applied for a patent related to BCAA used in 
      this study (Patent name: Agent for enhancing the antitumor activity of 
      chemotherapeutic drug, Patent application No: WO2012/111790). SN, MH and SI are 
      employed by Ajinomoto Pharmaceuticals, Co, Ltd. This study is conducted on animal 
      models and has no direct implications on human subjects. However, the work of 
      this study will be translated to human subjects in future studies and hence this 
      publication may add some benefit to Ajinomoto Pharmaceuticals, Co, Ltd. There are 
      no further patents, products in development to declare. Compounding ratio of BCAA 
      used in this study is same as a compounding ratio of BCAA granules which are sold 
      by Ajinomoto Pharmaceuticals Co. Ltd. in Japan by the name of LIVACT (R) Granules. 
      However, the company doesn't draw a direct commercial benefit from this study as 
      it is not conducted in human subjects. This does not alter the authors' adherence 
      to all the PLOS ONE policies on sharing data and materials.
EDAT- 2013/12/07 06:00
MHDA- 2014/08/06 06:00
PMCR- 2013/11/27
CRDT- 2013/12/07 06:00
PHST- 2013/07/28 00:00 [received]
PHST- 2013/10/31 00:00 [accepted]
PHST- 2013/12/07 06:00 [entrez]
PHST- 2013/12/07 06:00 [pubmed]
PHST- 2014/08/06 06:00 [medline]
PHST- 2013/11/27 00:00 [pmc-release]
AID - PONE-D-13-30802 [pii]
AID - 10.1371/journal.pone.0082346 [doi]
PST - epublish
SO  - PLoS One. 2013 Nov 27;8(11):e82346. doi: 10.1371/journal.pone.0082346. 
      eCollection 2013.