RRC ID 36964
著者 Obara A, Fujita Y, Abudukadier A, Fukushima T, Oguri Y, Ogura M, Harashima S, Hosokawa M, Inagaki N.
タイトル DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells.
ジャーナル Biochem Biophys Res Commun
Abstract Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy.
巻・号 460(4)
ページ 1047-52
公開日 2015-5-15
DOI 10.1016/j.bbrc.2015.03.148
PII S0006-291X(15)00616-6
PMID 25843797
MeSH Base Sequence Cell Line, Tumor DNA Primers Humans Intracellular Signaling Peptides and Proteins / metabolism* Liver Neoplasms / drug therapy* Liver Neoplasms / metabolism Liver Neoplasms / pathology Metformin / therapeutic use* Phosphorylation Polymerase Chain Reaction Ribosomal Protein S6 Kinases / metabolism Signal Transduction TOR Serine-Threonine Kinases / metabolism*
IF 2.985
引用数 16
WOS 分野 BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 Hep G2 HuH-7