PMID- 18006825
OWN - NLM
STAT- MEDLINE
DCOM- 20071203
LR  - 20220409
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 22
DP  - 2007 Nov 15
TI  - Metformin inhibits mammalian target of rapamycin-dependent translation initiation 
      in breast cancer cells.
PG  - 10804-12
AB  - Metformin is used for the treatment of type 2 diabetes because of its ability to 
      lower blood glucose. The effects of metformin are explained by the activation of 
      AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. 
      Recently, we showed that metformin inhibits the growth of breast cancer cells 
      through the activation of AMPK. Here, we show that metformin inhibits translation 
      initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% 
      decrease in global protein synthesis. Metformin caused a dose-dependent specific 
      decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome 
      profile analysis showed an inhibition of translation initiation as metformin 
      treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes 
      and a concomitant increase in the amount of 80S ribosomes. The decrease in 
      translation caused by metformin was associated with mammalian target of rapamycin 
      (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal 
      protein S6, and eIF4E-binding protein 1. The effects of metformin on translation 
      were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C 
      prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 
      cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null 
      (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating 
      that LKB1 and TSC2 are involved in the mechanism of action of metformin. These 
      results show that metformin-mediated AMPK activation leads to inhibition of mTOR 
      and a reduction in translation initiation, thus providing a possible mechanism of 
      action of metformin in the inhibition of cancer cell growth.
FAU - Dowling, Ryan J O
AU  - Dowling RJ
AD  - Department of Biochemistry, McGill Cancer Centre, Montreal, Quebec, Canada.
FAU - Zakikhani, Mahvash
AU  - Zakikhani M
FAU - Fantus, I George
AU  - Fantus IG
FAU - Pollak, Michael
AU  - Pollak M
FAU - Sonenberg, Nahum
AU  - Sonenberg N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Multienzyme Complexes)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
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
MH  - Animals
MH  - Breast Neoplasms/*metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Genes, Reporter
MH  - Humans
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Models, Biological
MH  - Multienzyme Complexes/*metabolism
MH  - Polyribosomes/metabolism
MH  - Protein Biosynthesis/drug effects
MH  - Protein Kinases/*physiology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Ribosomes/metabolism
MH  - TOR Serine-Threonine Kinases
EDAT- 2007/11/17 09:00
MHDA- 2007/12/06 09:00
CRDT- 2007/11/17 09:00
PHST- 2007/11/17 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/11/17 09:00 [entrez]
AID - 67/22/10804 [pii]
AID - 10.1158/0008-5472.CAN-07-2310 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Nov 15;67(22):10804-12. doi: 10.1158/0008-5472.CAN-07-2310.