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Modulation of the activities of AMP‐activated protein kinase, protein kinase B, and mammalian target of rapamycin by limiting energy availability with 2‐deoxyglucose
Author(s) -
Jiang Weiqin,
Zhu Zongjian,
Thompson Henry J.
Publication year - 2008
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20425
Subject(s) - biology , pi3k/akt/mtor pathway , ampk , protein kinase b , protein kinase a , rptor , phosphorylation , p70 s6 kinase 1 , kinase , amp activated protein kinase , microbiology and biotechnology , signal transduction
2‐Deoxyglucose (2‐DG), which has been shown to inhibit mammary carcinogenesis, was used as a metabolic probe to investigate effects of limiting energy availability (reduced cellular ATP) on patterns of proteins' phosphorylation that play a role in the development of cancer. Experiments were conducted using a human breast cancer cell line, MDA‐MB‐468, and 1‐methyl‐1‐nitrosourea‐induced rat model for mammary carcinogenesis. Under in vitro conditions in which cellular ATP concentration decreased rapidly with increasing 2‐DG in a dose and time dependent manner, levels of phosphorylated mammalian target of rapamycin (P‐mTOR) decreased in parallel to decreases in ATP concentration. Concomitantly, phosphorylation of two upstream regulators of mTOR, AMP‐activated protein kinase (AMPK) and Akt/protein kinase B were increased and decreased, respectively, with increased levels of phosphorylated acetyl‐CoA carboxylase as an indicator of AMPK activation. Levels of insulin like growth factor 1‐receptor and phosphoinositide‐3 kinase p110α were also reduced. Similar effects were observed in mammary carcinomas in vivo at concentration of 0.03% (w/w) dietary 2‐DG that inhibited carcinogenesis. In vitro, downregulation of mTOR was accompanied by decreases in phosphorylation of two of mTOR's targets, 70‐kDa ribosomal protein S6 kinase and eukaryote initiation factor 4E binding protein 1. Glucose treatment reversed 2‐DG effects. When cells were transfected with dominant‐negative AMPKα2, effects of 2‐DG on mTOR and its downstream effectors were diminished, providing evidence of a link between AMPK and mTOR when energy availability was limited. This work indicates that AMPK, Akt, and mTOR are candidate targets for efforts to inhibit the carcinogenic process by limiting energy availability. © 2008 Wiley‐Liss, Inc.