ReviewmTOR: Role in cancer, metastasis and drug resistance
Introduction
Rapamycin is a natural macrolide with antifungal, antiproliferative, and immunosuppressive properties which was originally discovered from the bacteria Streptomyces hygroscopicus in soil samples by Surendra Nath Sehgal and his group when they traveled to Easter Island (it was known as Rapa Nui by locals) in 1964 [1]. Three decades later, two genes (TOR1 and TOR2) were identified as a direct target of the immunosuppressant, rapamycin toxicity in yeast cells by MN Hall and his colleagues in 1991 [2]. After three years, the mTOR protein was discovered as a direct target of rapamycin-FKBP12 (12 kDa FK506-binding protein) complex in mammalian cells, called mammalian target of rapamycin (mTOR). This discovery came independently from three different labs, SL Schreiber and SH Snyder’s lab demonstrated in mid-1994 while RT Abraham lab reported in early 1995 [[3], [4], [5]]. These studies confirmed the previously-identified yeast TOR to be the homolog of mTOR. Since then pioneering discoveries in this area were made by many labs from all over the world. In particular, the molecular and biochemical approach uncovered various binding partners, downstream/upstream effectors, signaling mediators of mTOR and its role in the biological process which was recently reviewed by DM Sabatini [6]. In a normal cell, mTOR gets various environmental stimuli from amino acids, growth factors, oxygen, stress, redox sensors, and energy. In response to these diverse environmental cues, the active mTOR promotes cellular anabolism to generate various macromolecules such as nucleic acids, proteins, lipids which build cellular biomass, ribosome biogenesis, and protein translation. mTOR also blocks catabolic processes including lysosome biogenesis and autophagy and it is a master regulator of cellular metabolism. The mTOR integrates these wide ranges of environmental cues-induced anabolic processes to modulate metabolic pathways for cell proliferation, growth, and metabolism. The mTOR also plays a central role in the regulation of autophagy [7].
Cancer is a multifactorial and complex disease and known to be the most leading causes of human deaths worldwide. Phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR pathway is one of the most deregulated signaling pathways in human cancer. The mTOR is considered as a master regulator of this signaling pathway and recent findings reported that the mTOR has a pivotal role in human cancer when it is activated. Further, mTOR signaling is often reported to be hyperactivated in the majority of human cancers particularly implicated in the cell transformation, growth, survival, etc [[7], [8], [9]].
Section snippets
Structure of mTOR
mTOR is a 288.892 kDa serine/threonine protein kinase that comprises 2550 amino acids (including stop codon) which are encoded by 7650 nucleotides and the mTOR gene is located in chromosome 1 (1p36.22). The mTOR basically belongs to PI3K-related kinases (PIKK) and most of the PIKK members have conserved domain architecture [10,11]. The mTOR protein molecule has a large N-terminal α-solenoid (HEAT repeats), a FAT (FRAP, ATM, TRRAP) domain, KD (a protein kinase domain), and an FRB
Upstream and downstream signaling of mTORC1 and mTORC2
Growth factor-mediated RTKs (receptor tyrosine kinases)/PI3K/Akt signaling pathway is an important upstream signaling pathway of the mTOR protein molecule [28]. In response to various extracellular stimuli such as growth factors, nutrients, and amino acids, mTOR strongly associates to various protein molecules and to form two distinct multiprotein molecular complexes such as mTORC1 and mTORC2, and regulates various growth signals by directly phosphorylating the immediate substrates [29]. In a
Biological functions of mTOR
The mTOR is a multifaceted protein molecule and is a catalytic core component of Raptor-mTOR (mTORC1) and Rictor-mTOR (mTORC2) complexes known to function both as a serine/threonine kinase and tyrosine kinase, respectively [41]. The mTOR is demonstrated to play a key role in early embryonic development particularly in pluripotency and T-cell transdifferentiation [45,46]. As seen in Fig. 1, the mTORC1 plays a central role in metabolic homeostasis, protein, and lipid synthesis, glycolysis,
Deregulated mTOR in human diseases
The mTOR signaling has a broader impact on basic vital cellular functions and its deregulated signaling alters normal physiological functions that result in pathogenesis in humans. Moreover, deregulated mTOR is displayed to be implicated in human growth and metabolic diseases including neuronal degeneration, obesity, type 2 diabetes, and cancer [7,9,49].
Activation of mTOR by upstream signaling molecules in human cancer
The RTKs-mediated PI3K activation phosphorylates and switches PIP2 to PIP3 (directly antagonized by the tumor suppressor, PTEN by dephosphorylating the PIP3 to PIP2) that drives PI3K signaling cascade which feeds onto both mTORC1 and mTORC2 complexes. Amplifications and genetic mutations are the common genetic changes that constitutively activate the protein molecules. Either activation of RTKs or the other upstream members such as PIK3CA, RAS (H, K, and NRAS), Akt and loss of PTEN molecules
Hyperactivating mutations of mTOR gene
Initially, the hyperactivation of mTOR was observed by Abraham and his group. When the mTOR mutant (named as ΔTOR-deletion mutant) was generated with unimpaired phosphorylation site for Akt (2430–2450 amino acids close to the carboxyl terminus of the mTOR) and overexpressed in HEK293 cells, they found that mutant could enhance a 3.5-fold of its basal protein kinase activity resulting in phosphorylation of p70S6K and mTOR-mediated in vivo signaling. This group also found that mTOR is the direct
Prevalence of mTOR mutations in human cancer
Analysis of the COSMIC database displayed that the incidence of mTOR mutations greatly varies among the different types of cancer. The highest frequency was detected in 28.57% (2/7) and 33.3% (1/3) of the fallopian tube, penis cancer, respectively. Nonetheless, the number of tumors analyzed for mTOR mutation was relatively very low and hence raise the skepticism about the incidence of mutation. Several other cancer types follow with a considerably higher incidence of mTOR mutations consisting
Oncogenic mutations of mTOR in human cancers
Although somatic mutations were earlier identified in the mTOR gene, Sato et al were the first to functionally characterize the cancer-associated mTOR mutation in vitro. Their study selected human cancer-associated mTOR mutations (A8S, S2215Y, P2476L and R2505P) from the COSMIC database and introduced them in the mTOR gene using site-directed mutagenesis. Transient overexpression of each of these mutants in HEK293T cells revealed enhanced protein kinase activity, and hyperactivation of
Mechanisms of mutation-mediated activation of mTOR
The mechanism of mutant-induced mTOR activation is not exclusively studied and clearly understood. However, it has been speculated that mutations harboring in the kinase domain and close to the activation loop are likely to alter the conformation that may result in enhanced kinase activities [119]. Further, Grabiner et al contemplated that mutation might distort the mTORC1 or mTORC2 assembly which results in enhanced p70S6K1/Akt1 phosphorylation, respectively or mutant mTOR may mislay the
The mTOR is a driver of invasion and metastasis
Most of the cancer deaths occur because of the metastasis of the primary tumor to the multiple organs. Acquiring the migratory and invasive potential is the initial step and that is the rate-limiting primary step in the metastasis cascade. Epithelial-mesenchymal transition (EMT) is found to be the critical mechanism in the primary step in the metastatic process because during this molecular program epithelial cells undergo various steps by losing polarized. Differentiated phenotypes have many
The mTOR inhibitors: rapamycin
The PI3K/Akt/mTOR signaling pathway is one of the most commonly deregulated pathways found in human cancers that supplied the rationale for therapeutically targeting mTOR in cancer [47,39]. Subsequent research activities led to synthesize and develop several small-molecule inhibitors that could target many active molecules in the pathway. Indeed, as of today, only the mTOR inhibitors were the first small molecules which were translated from bench to bedside to target the PI3K/Akt/mTOR pathway [
Drug resistance in human cancers: the pivotal role of mTOR
Precision medicine facilitates molecular targeted therapy and eases the therapeutic management. Tumors which tend to develop drug resistance during the course of treatment that complicates the subsequent management. Understanding and resolving the resistance mechanism is more complex as most resistance arises due to the activation of upstream/downstream molecules upon molecular targeted therapy. Further, resistance also arises due to the multi-clonal origin of tumors and heterogeneity in
The mTOR and precision medicine
Focusing on individual genetic variations, environment, and lifestyle intending to prevent and treat various human diseases is a new strategy called precision medicine or personalized medicine. Recent genetic techniques particularly the next-generation sequencing technologies along with computational technology facilitated whole genome, exome and transcriptome sequencing which gathered genomic data on human diseases that rapidly altered drastic changes in the treatment strategies which paved
Conclusions and future prospective
The mTOR and its signaling pathway are implicated in a wide range of normal physiological functions. In a variety of human cancers, the mTOR signaling pathway is commonly deregulated either due to the genomic alterations resulting in hyperactivation of an upstream/downstream signaling pathway or hyperactivation of mTOR that in turn provides an analogous impact. mTOR mutations have essential implication not only in the pathogenesis of cancer but also in inducing resistance to the mTOR
Funding
This study was not funded.
Declaration of Competing Interest
Author, AK Murugan has no conflict of interest to declare except that he is the guest editor of this special issue, “PI3K/Akt Signaling in Human Cancer” in Seminars in Cancer Biology.
Acknowledgments
I thank all the researchers in this field whose valuable work provided me a delightful reading experience and apologize to my colleagues whose work could not be cited primarily due to space constraints.
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