PMID- 23526220
OWN - NLM
STAT- MEDLINE
DCOM- 20130930
LR  - 20240104
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Linking)
VI  - 49
IP  - 2
DP  - 2013 Aug
TI  - Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and 
      activator of transcription-3 activity independently of the liver kinase 
      B1-AMP-activated protein kinase pathway.
PG  - 241-50
LID - 10.1165/rcmb.2012-0244OC [doi]
AB  - Metformin has been used as first-line treatment in patients with type 2 diabetes, 
      and is reported to reduce cancer risk and progression by activating the liver 
      kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Cisplatin remains 
      the main drug for treating advanced non-small-cell lung cancer. However, drug 
      resistance often develops through several mechanisms during the treatment course, 
      including one mechanism mediated by the activation of the IL-6/signal transducer 
      and activator of transcription (STAT)-3 pathway, related to the generation of 
      reactive oxygen species (ROS). This study demonstrated a correlation between 
      STAT3 phosphorylation and cisplatin cytotoxicity, using AS2 (PC14PE6/AS2)-derived 
      cell lines (AS2/S3C) that contained constitutively active STAT3 plasmids as a 
      model. A STAT3 inhibitor (JSI-124) enhanced the cisplatin sensitivity in AS2 
      cells, whereas metformin inhibited STAT3 phosphorylation and enhanced cisplatin 
      cytotoxicity. By contrast, another AMPK activator 
      (5-aminoimidazole-4-carboxamide-riboside) failed to produce these effects. 
      LKB1-AMPK silencing by small, interfering RNA or mammalian target of rapamycin 
      (mTOR) inhibition by rapamycin or pp242 did not alter the effect of metformin on 
      STAT3 activity suppression, suggesting that metformin can modulate the STAT3 
      pathway through an LKB1-AMPK-independent and probably mTOR-independent mechanism. 
      Metformin also inhibited cisplatin-induced ROS production and autocrine IL-6 
      secretion in AS2 cells. Both mechanisms contributed to the ability of metformin 
      to suppress STAT3 activation in cancer cells, which resulted in the decreased 
      secretion of vascular endothelial growth factor by cancer cells. The growth of 
      subcutaneous tumor xenografts was significantly delayed by a combination of 
      cisplatin and metformin. This is the first study to demonstrate that metformin 
      suppresses STAT3 activation via LKB1-AMPK-mTOR-independent but ROS-related and 
      autocrine IL-6 production-related pathways. Thus, metformin helps to overcome 
      tumor drug resistance by targeting STAT3.
FAU - Lin, Chien-Chung
AU  - Lin CC
AD  - Institute of Clinical Medicine, National Cheng Kung University Hospital, College 
      of Medicine, National Cheng Kung University, Tainan, Taiwan.
FAU - Yeh, Hsuan-Heng
AU  - Yeh HH
FAU - Huang, Wei-Lun
AU  - Huang WL
FAU - Yan, Jing-Jou
AU  - Yan JJ
FAU - Lai, Wu-Wei
AU  - Lai WW
FAU - Su, Wen-Pin
AU  - Su WP
FAU - Chen, Helen H W
AU  - Chen HH
FAU - Su, Wu-Chou
AU  - Su WC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - AMP-Activated Protein Kinases/genetics/*metabolism
MH  - Animals
MH  - Antineoplastic Agents/agonists/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cisplatin/agonists/*pharmacology
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Drug Synergism
MH  - Gene Silencing
MH  - Humans
MH  - Hypoglycemic Agents/agonists/*pharmacology
MH  - Interleukin-6/genetics/metabolism
MH  - Lung Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Metformin/agonists/*pharmacology
MH  - Mice
MH  - Mice, SCID
MH  - Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - STAT3 Transcription Factor/genetics/*metabolism
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - Vascular Endothelial Growth Factor A/genetics/metabolism
MH  - Xenograft Model Antitumor Assays
EDAT- 2013/03/26 06:00
MHDA- 2013/10/01 06:00
CRDT- 2013/03/26 06:00
PHST- 2013/03/26 06:00 [entrez]
PHST- 2013/03/26 06:00 [pubmed]
PHST- 2013/10/01 06:00 [medline]
AID - rcmb.2012-0244OC [pii]
AID - 10.1165/rcmb.2012-0244OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2013 Aug;49(2):241-50. doi: 10.1165/rcmb.2012-0244OC.