PMID- 27396756
OWN - NLM
STAT- MEDLINE
DCOM- 20170509
LR  - 20211204
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 116
DP  - 2016 Sep 15
TI  - Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK.
PG  - 39-50
LID - S0006-2952(16)30170-8 [pii]
LID - 10.1016/j.bcp.2016.07.005 [doi]
AB  - Ciclopirox olamine (CPX), an off-patent antifungal agent, has recently been 
      identified as a potential anticancer agent. The mammalian target of rapamycin 
      (mTOR) is a central controller of cell growth, proliferation and survival. Little 
      is known about whether and how CPX executes its anticancer action by inhibiting 
      mTOR. Here we show that CPX inhibited the phosphorylation of p70 S6 kinase 1 
      (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two 
      downstream effector molecules of mTOR complex 1 (mTORC1), in a spectrum of human 
      tumor cells, indicating that CPX inhibits mTORC1 signaling. Using 
      rhabdomyosarcoma cells as an experimental model, we found that expression of 
      constitutively active mTOR (E2419K) conferred resistance to CPX inhibition of 
      cell proliferation, suggesting that CPX inhibition of mTORC1 contributed to its 
      anticancer effect. In line with this, treatment with CPX inhibited tumor growth 
      and concurrently suppressed mTORC1 signaling in RD xenografts. Mechanistically, 
      CPX inhibition of mTORC1 was neither via inhibition of IGF-I receptor or 
      phosphoinositide 3-kinase (PI3K), nor by activation of phosphatase and tensin 
      homolog (PTEN). Instead, CPX inhibition of mTORC1 was attributed to activation of 
      AMP-activated protein kinase (AMPK)-tuberous sclerosis complexes (TSC)/raptor 
      pathways. This is supported by the findings that CPX activated AMPK; inhibition 
      of AMPK with Compound C or ectopic expression of dominant negative AMPKalpha 
      partially prevented CPX from inhibiting mTORC1; silencing TSC2 attenuated CPX 
      inhibition of mTORC1; and CPX also increased AMPK-mediated phosphorylation of 
      raptor (S792). Therefore, the results indicate that CPX exerts the anticancer 
      effect by activating AMPK, resulting in inhibition of mTORC1 signaling.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Zhou, Hongyu
AU  - Zhou H
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; 
      Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA; Yunnan Key Laboratory of 
      Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of 
      Sciences, Kunming 650201, China.
FAU - Shang, Chaowei
AU  - Shang C
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA; Feist-Weiller Cancer 
      Center, Louisiana State University Health Sciences Center, Shreveport, LA 
      71130-3932, USA.
FAU - Wang, Min
AU  - Wang M
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; Yunnan 
      Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, 
      Chinese Academy of Sciences, Kunming 650201, China.
FAU - Shen, Tao
AU  - Shen T
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA; Feist-Weiller Cancer 
      Center, Louisiana State University Health Sciences Center, Shreveport, LA 
      71130-3932, USA.
FAU - Kong, Lingmei
AU  - Kong L
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; Yunnan 
      Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, 
      Chinese Academy of Sciences, Kunming 650201, China.
FAU - Yu, Chunlei
AU  - Yu C
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; 
      University of the Chinese Academy of Sciences, Beijing 100049, China.
FAU - Ye, Zhennan
AU  - Ye Z
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
FAU - Luo, Yan
AU  - Luo Y
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA.
FAU - Liu, Lei
AU  - Liu L
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA.
FAU - Li, Yan
AU  - Li Y
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; Yunnan 
      Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, 
      Chinese Academy of Sciences, Kunming 650201, China. Electronic address: 
      liyanb@mail.kib.ac.cn.
FAU - Huang, Shile
AU  - Huang S
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA; Feist-Weiller Cancer 
      Center, Louisiana State University Health Sciences Center, Shreveport, LA 
      71130-3932, USA. Electronic address: shuan1@lsuhsc.edu.
LA  - eng
GR  - R01 CA115414/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160707
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Pyridones)
RN  - 0 (Recombinant Proteins)
RN  - 19W019ZDRJ (Ciclopirox)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/chemistry/genetics/*metabolism
MH  - Animals
MH  - Antineoplastic Agents/adverse effects/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - Ciclopirox
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Activation/drug effects
MH  - Female
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice, Nude
MH  - Multiprotein Complexes/*antagonists & inhibitors/genetics/metabolism
MH  - Neoplasm Proteins/agonists/antagonists & inhibitors/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Processing, Post-Translational/drug effects
MH  - Pyridones/adverse effects/pharmacology/*therapeutic use
MH  - Random Allocation
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Rhabdomyosarcoma/*drug therapy/metabolism/pathology
MH  - Signal Transduction/*drug effects
MH  - Specific Pathogen-Free Organisms
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC5003681
MID - NIHMS801456
OTO - NOTNLM
OT  - AMPK
OT  - Ciclopirox
OT  - Raptor
OT  - TSC2
OT  - mTOR
COIS- The authors declare no conflict of interest.
EDAT- 2016/07/12 06:00
MHDA- 2017/05/10 06:00
PMCR- 2017/09/15
CRDT- 2016/07/12 06:00
PHST- 2016/04/30 00:00 [received]
PHST- 2016/07/06 00:00 [accepted]
PHST- 2016/07/12 06:00 [entrez]
PHST- 2016/07/12 06:00 [pubmed]
PHST- 2017/05/10 06:00 [medline]
PHST- 2017/09/15 00:00 [pmc-release]
AID - S0006-2952(16)30170-8 [pii]
AID - 10.1016/j.bcp.2016.07.005 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2016 Sep 15;116:39-50. doi: 10.1016/j.bcp.2016.07.005. Epub 
      2016 Jul 7.