title: Hyperactivation of 4E-binding protein 1 as a mediator of biguanide-induced cytotoxicity during glucose deprivation.
abstract: 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can be mediated by 4E-BP1 hyperactivation, which results in UPR inhibition and selective cell killing when glucose is withdrawn.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.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsuo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsukumo
authors.forename: Sakae
authors.initials: S
authors.lastname: Saito
authors.forename: Satomi
authors.initials: S
authors.lastname: Tsukahara
authors.forename: Junko
authors.initials: J
authors.lastname: Sakurai
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kondo
authors.forename: Masaru
authors.initials: M
authors.lastname: Ushijima
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuura
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001645:Biguanides / Q000633:toxicity*; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001645:Biguanides; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D058570:TOR Serine-Threonine Kinases; D005947:Glucose