5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells

Cell Cycle
Suman MukhopadhyayD A Foster

Abstract

mTOR - the mammalian/mechanistic target of rapamycin - has been implicated as a key signaling node for promoting survival of cancer cells. However, clinical trials that have targeted mTOR with rapamycin or rapamycin analogs have had minimal impact. In spite of the high specificity of rapamycin for mTOR, the doses needed to suppress key mTOR substrates have proved toxic. We report here that rapamycin when combined with AICAR - a compound that activates AMP-activated protein kinase makes rapamycin cytotoxic rather than cytostatic at doses that are tolerated clinically. AICAR by itself is able to suppress mTOR complex 1 (mTORC1), but also stimulates a feedback activation of mTORC2, which activates the survival kinase Akt. However, AICAR also suppresses production of phosphatidic acid (PA), which interacts with mTOR in a manner that is competitive with rapamycin. The reduced level of PA sensitizes mTORC2 to rapamycin at tolerable nano-molar doses leading reduced Akt phosphorylation and apoptosis. This study reveals how the use of AICAR enhances the efficacy of rapamycin such that rapamycin at low nano-molar doses can suppress mTORC2 and induce apoptosis in human cancer cells at doses that are clinically tolerable.

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Citations

Feb 19, 2019·Oncotarget·Colin Rae, Robert J Mairs
May 2, 2020·International Journal of Molecular Sciences·Alia GhoneumNeveen Said
Mar 14, 2019·International Journal of Molecular Medicine·Jin Sun LeeYoung Bok Ko
Nov 27, 2019·International Journal of Molecular Sciences·Azzurra IrelliMassimo De Martinis
May 23, 2020·OncoTargets and Therapy·Liangyuan LongWeiying Zhou
Feb 27, 2016·Molecular Cancer Therapeutics·Suman MukhopadhyayDavid A Foster
Feb 13, 2021·International Journal of Molecular Sciences·Nadezhda V Popova, Manfred Jücker
Jan 28, 2021·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Zhiqin ZhangXiaoyan Wu
Mar 7, 2021·International Journal of Molecular Sciences·George KyriakopoulosConstantinos Stathopoulos
Apr 3, 2021·Cancer Cell International·Zeeshan JavedJavad Sharifi-Rad
Jun 3, 2021·International Journal of Molecular Sciences·Maria NamwanjeAmandeep Bajwa
Jun 25, 2021·Journal of Experimental & Clinical Cancer Research : CR·Jingjing YangJichun Zhou
Jul 3, 2021·International Journal of Molecular Sciences·Milad GhomlaghiLan K Nguyen

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Methods Mentioned

BETA
flow cytometry
light microscopy
immunoprecipitation
GTPase
scraping

Software Mentioned

LI
COR studio
COR image studio
WinCycle

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