Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1

Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2011-07, Vol.71 (13), p.4366-4372
Main Authors: ISAAM BEN SAHRA, REGAZZETTI, Claire, ROBERT, Guillaume, LAURENT, Kathiane, LE MARCHAND-BRUSTEL, Yannick, AUBERGER, Patrick, TANTI, Jean-François, GIORGETTI-PERALDI, Sophie, BOST, Frédéric
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - metabolism
Animals
Antineoplastic agents
Biological and medical sciences
Cell Cycle - drug effects
Cell Cycle - physiology
Cell Line, Tumor
Cyclin D1 - metabolism
Humans
Male
Medical sciences
Metformin - pharmacology
Mice
Mice, Transgenic
Pharmacology. Drug treatments
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
RNA, Messenger - biosynthesis
RNA, Messenger - genetics
RNA, Small Interfering - genetics
TOR Serine-Threonine Kinases - antagonists & inhibitors
Transcription Factors - biosynthesis
Transcription Factors - genetics
Transfection
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary:Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-10-1769