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Title: DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

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,more » 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. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.« less

Authors:
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Publication Date:
OSTI Identifier:
22462050
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 460; Journal Issue: 4; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AUGMENTATION; CELL PROLIFERATION; DRUGS; HUMAN POPULATIONS; INHIBITION; LIVER; NEOPLASMS; PATIENTS; PHOSPHORYLATION; PROTEINS; SIGNALS; SUBSTRATES; THERAPY

Citation Formats

Obara, Akio, Fujita, Yoshihito, Abudukadier, Abulizi, Fukushima, Toru, Oguri, Yasuo, Ogura, Masahito, Harashima, Shin-ichi, Hosokawa, Masaya, and Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.03.148.
Obara, Akio, Fujita, Yoshihito, Abudukadier, Abulizi, Fukushima, Toru, Oguri, Yasuo, Ogura, Masahito, Harashima, Shin-ichi, Hosokawa, Masaya, & Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells. United States. doi:10.1016/J.BBRC.2015.03.148.
Obara, Akio, Fujita, Yoshihito, Abudukadier, Abulizi, Fukushima, Toru, Oguri, Yasuo, Ogura, Masahito, Harashima, Shin-ichi, Hosokawa, Masaya, and Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp. Fri . "DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells". United States. doi:10.1016/J.BBRC.2015.03.148.
@article{osti_22462050,
title = {DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells},
author = {Obara, Akio and Fujita, Yoshihito and Abudukadier, Abulizi and Fukushima, Toru and Oguri, Yasuo and Ogura, Masahito and Harashima, Shin-ichi and Hosokawa, Masaya and Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp},
abstractNote = {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. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.},
doi = {10.1016/J.BBRC.2015.03.148},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 460,
place = {United States},
year = {2015},
month = {5}
}