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.

Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo

“…Various miRNAs are involved in the regulation of inflammatory responses, including those that target the mTOR pathway . We screened several miRNAs implicated in mTOR signaling, and observed induction of miR‐126 and Let‐7a by mango treatment, compared with controls (Figure E).…”

“…MicroRNAs (miRNAs) are emerging as a potential link between inflammation and cancer by inducing mRNA degradation or blocking translation of key molecular targets involved in IBD . Moreover, polyphenolics are known to influence the post‐transcriptional regulation of miRNAs , with the mTOR pathway serving as a promising target for the anti‐cancer properties of miRNAs . For example, miR‐126 targets phosphatidylinositol 3‐kinase regulatory subunit beta (PI3Kp85β), an upstream regulator of the mTOR pathway .…”

Preliminary analysis of different microRNA expression levels in juvenile angiofibromas

“…In this context, miRNA 218 can induce, via inhibition of Akt, the inhibition of GSK-3β. This effect results in stabilization and further translocation of β-catenin from the cytoplasm to the nucleus leading to specific gene activations (6,23,24). As the frequently observed β-catenin mutations in JAs have been previously indicated to result in nuclear accumulation of stabilized β-catenin, the present finding of miRNA 218 downregulation represents a further pathway leading to nuclear accumulation of β-catenin in JAs and also in other tumor entities.…”

Roles and clinical implications of microRNAs in acute lymphoblastic leukemia

“…miRNAs are important regulators of key genes in the PI3K/Akt/mTOR pathway, suggesting miRNAs as a new therapeutic target also in leukemia (AlQurashi, Hashimi, & Wei, ). It was shown in promyelocytic cell line NB4 that miR‐223 is able to reduce cell growth by the inhibition of the insulin‐like growth factor 1 receptor (IGF1‐R), blocking PI3K signal (Jia et al, ) (Figure ).…”