Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives.
The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.
Department of Pharmacy, Faculty of Science, National University of Singapore Singapore, Singapore.
Pei Shi
PS
Ong
Department of Pharmacy, Faculty of Science, National University of SingaporeSingapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.
Louis Z
LZ
Wang
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
Xiaoyun
X
Dai
Department of Pharmacy, Faculty of Science, National University of Singapore Singapore, Singapore.
Sheng Hsuan
SH
Tseng
Department of Pharmacy, Faculty of Science, National University of Singapore Singapore, Singapore.
Shang Jun
SJ
Loo
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.
Gautam
G
Sethi
cancer; cancer stem cell; chemoresistance; insulin resistance; mechanistic target of rapamycin; mechanistic target of rapamycin inhibitors; rapamycin