Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics

Abstract

The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics.

Figure 1

Schematic representation of the mTOR domain, mTORC1 and mTORC2 complexes. (A) The domain structure of mTOR is composed of HEAT repeats and FAT followed by FRB (a unique feature of mTOR that serves as the binding site for the inhibitory FKBP12 rapamycin complex), a kinase domain and the FATC (FAT C-terminus) domain. (B,C) mTOR complex 1 (mTORC1) and mTORC2 consist of shared and unique components. mTOR, mLST8 and DEPTOR are shared between the two complexes whereas RAPTOR and PRAS40 are unique to mTORC1. RICTOR, mSIN1 and PROTOR are unique to mTORC2.

Figure 2

mTOR signalling pathway. mTORC1 activates S6K and inhibits 4E-BP in response to extracellular (growth factors, amino acids, glucose and cellular conditions) and intracellular signals (PI3K, AKT, PDK1, TSC1/2, AMPK, Rheb and Rag GTPases), resulting in activation of protein synthesis and suppression of autophagy. mTORC2 regulates apoptosis by phosphorylation of Akt at Ser473 and SGK. Green arrows represent activation, whereas the red represent inhibition; the green P represents activation through phosphorylation, whereas the red P represents inhibition through phosphorylation. Broken red lines indicate indirect inhibition.

Figure 3

Regulatory networks of mTOR inhibitors and miRNAs in controlling the mTOR pathway in cancer. Green microRNAs (miRNAs) represent oncogenic activities, whereas the red represent tumour suppressor activities. Green lines indicate activation, whereas the red indicate inhibition.