Hyperactivation of 4E-binding protein 1 as a mediator of biguanide-induced cytotoxicity during glucose deprivation

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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14 Citations (Scopus)

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can be mediated by 4E-BP1 hyperactivation, which results in UPR inhibition and selective cell killing when glucose is withdrawn.

Original languageEnglish
Pages (from-to)1082-1091
Number of pages10
JournalMolecular Cancer Therapeutics
Volume11
Issue number5
DOIs
Publication statusPublished - 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Matsuo, J., Tsukumo, Y., Saito, S., Tsukahara, S., Sakurai, J., Sato, S., Kondo, H., Ushijima, M., Matsuura, M., Watanabe, T., & Tomida, A. (2012). Hyperactivation of 4E-binding protein 1 as a mediator of biguanide-induced cytotoxicity during glucose deprivation. Molecular Cancer Therapeutics, 11(5), 1082-1091. https://doi.org/10.1158/1535-7163.MCT-11-0871