Document Detail


Hyperactivation of 4E-binding protein 1 as a mediator of biguanide-induced cytotoxicity during glucose deprivation.
MedLine Citation:
PMID:  22402126     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Biguanides, including metformin, buformin and phenformin, are potential antitumorigenic agents and induce cell death during glucose deprivation, a cell condition that occurs in the tumor microenvironment. Here, we show that this selective killing of glucose-deprived cells is coupled with hyperactivation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation initiation. We found, in fact, that the 4E-BP1 hyperactivation led to failure of the unfolded protein response (UPR), an endoplasmic reticulum-originated stress signaling pathway for cell survival. We also found that the 4E-BP1-mediated UPR inhibition occurred through a strong inhibition of the mTOR signaling pathway, a proven antitumor target. Importantly, the 4E-BP1 hyperactivation can be also seen in xenografted cancer cells through an in vivo biguanide treatment. Our findings indicate that antitumor action of biguanides can be mediated by 4E-BP1 hyperactivation, which results in UPR inhibition and selective cell killing when glucose is withdrawn.
Authors:
Junichi Matsuo; Yoshinori Tsukumo; Sakae Saito; Satomi Tsukahara; Junko Sakurai; Shigeo Sato; Hiromichi Kondo; Masaru Ushijima; Masaaki Matsuura; Toshiki Watanabe; Akihiro Tomida
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-8
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  -     ISSN:  1538-8514     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1The Cancer Chemotherpy Center, Japanese Foundation for Cancer Research.
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