PMID- 29949674
OWN - NLM
STAT- MEDLINE
DCOM- 20180918
LR  - 20211204
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 109
IP  - 9
DP  - 2018 Sep
TI  - Transcriptional repression of human epidermal growth factor receptor 2 by ClC-3 
      Cl(-) /H(+) transporter inhibition in human breast cancer cells.
PG  - 2781-2791
LID - 10.1111/cas.13715 [doi]
AB  - Recent studies have indicated that the intracellular concentration of chloride 
      ions (Cl(-) ) regulates gene expression in several types of cells and that Cl(-) 
      modulators positively or negatively regulate the PI3K/AKT/mammalian target of 
      rapamycin (mTOR) and signal transducer and activator of transcription (STAT)3 
      signaling pathways. We previously reported that the Ca(2+) -activated Cl(-) 
      channel anoctamine (ANO)1 regulated human epidermal growth factor receptor 2 
      (HER2) transcription in breast cancer YMB-1 cells. However, the mechanisms 
      underlying ANO1-regulated HER2 gene expression have not yet been elucidated. In 
      the present study, we showed the involvement of intracellular organelle ClC-3 
      Cl(-) /H(+) transporter in HER2 transcription in breast cancer MDA-MB-453 cells. 
      The siRNA-mediated inhibition of ClC-3, but not ANO1, markedly repressed HER2 
      transcription in MDA-MB-453 cells. Subsequently, treatments with the AKT 
      inhibitor AZD 5363 and mTOR inhibitor everolimus significantly enhanced HER2 
      transcription in MDA-MB-453 cells, whereas that with the STAT3 inhibitor 
      5,15-diphenylporphyrin (5,15-DPP) inhibited it. AKT and mTOR inhibitors also 
      significantly enhanced HER2 transcription in YMB-1 cells. The siRNA-mediated 
      inhibition of ClC-3 and ANO1 resulted in increased AKT phosphorylation and 
      decreased STAT3 phosphorylation in MDA-MB-453 and YMB-1 cells, respectively. The 
      intracellular Cl(-) channel protein CLIC1 was expressed in both cells; however, 
      its siRNA-mediated inhibition did not elicit the transcriptional repression of 
      HER2. Collectively, our results demonstrate that intracellular Cl(-) regulation 
      by ANO1/ClC-3 participates in HER2 transcription, mediating the PI3K/AKT/mTOR 
      and/or STAT3 signaling pathway(s) in HER2-positive breast cancer cells, and 
      support the potential of ANO1/ClC-3 blockers as therapeutic options for patients 
      with resistance to anti-HER2 therapies.
CI  - (c) 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Fujimoto, Mayu
AU  - Fujimoto M
AD  - Department of Pharmacology, Division of Pathological Sciences, Kyoto 
      Pharmaceutical University, Kyoto, Japan.
FAU - Kito, Hiroaki
AU  - Kito H
AD  - Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City 
      University, Nagoya, Japan.
FAU - Kajikuri, Junko
AU  - Kajikuri J
AD  - Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City 
      University, Nagoya, Japan.
FAU - Ohya, Susumu
AU  - Ohya S
AUID- ORCID: 0000-0002-5765-0667
AD  - Department of Pharmacology, Division of Pathological Sciences, Kyoto 
      Pharmaceutical University, Kyoto, Japan.
AD  - Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City 
      University, Nagoya, Japan.
LA  - eng
GR  - JP16K08285/JSPS KAKENHI/
PT  - Journal Article
DEP - 20180728
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (ANO1 protein, human)
RN  - 0 (Anoctamin-1)
RN  - 0 (Chloride Channels)
RN  - 0 (Chlorides)
RN  - 0 (ClC-3 channel)
RN  - 0 (Histones)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Anoctamin-1/physiology
MH  - Breast Neoplasms/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Chloride Channels/*physiology
MH  - Chlorides/metabolism
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Histones/metabolism
MH  - Humans
MH  - Neoplasm Proteins/physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Proto-Oncogene Proteins c-akt/physiology
MH  - Receptor, ErbB-2/*genetics
MH  - STAT3 Transcription Factor/physiology
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases/physiology
PMC - PMC6125433
OTO - NOTNLM
OT  - AKT
OT  - ClC-3
OT  - HER2
OT  - STAT3
OT  - breast cancer
EDAT- 2018/06/28 06:00
MHDA- 2018/09/19 06:00
PMCR- 2018/09/01
CRDT- 2018/06/28 06:00
PHST- 2018/04/10 00:00 [received]
PHST- 2018/06/23 00:00 [accepted]
PHST- 2018/06/28 06:00 [pubmed]
PHST- 2018/09/19 06:00 [medline]
PHST- 2018/06/28 06:00 [entrez]
PHST- 2018/09/01 00:00 [pmc-release]
AID - CAS13715 [pii]
AID - 10.1111/cas.13715 [doi]
PST - ppublish
SO  - Cancer Sci. 2018 Sep;109(9):2781-2791. doi: 10.1111/cas.13715. Epub 2018 Jul 28.