scholarly journals Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

2020 ◽  
Vol 21 (9) ◽  
pp. 3285 ◽  
Author(s):  
Choudhary Harsha ◽  
Kishore Banik ◽  
Hui Li Ang ◽  
Sosmitha Girisa ◽  
Rajesh Vikkurthi ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Therapeutic Interventions ◽  
Treatment Modalities ◽  
Disease Heterogeneity ◽  
Mesenchymal Transition

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

scholarly journals The Role of mTOR Signaling as a Therapeutic Target in Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1743
Author(s):  
Nadezhda V. Popova ◽  
Manfred Jücker
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Genetic Alterations ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Cell Processes ◽  
And Function ◽  
Available Information ◽  
Mtor Complex 1

The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

scholarly journals Salmonella Impacts Tumor-Induced Macrophage Polarization, and Inhibits SNAI1-Mediated Metastasis in Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2894
Author(s):  
Christian R. Pangilinan ◽  
Li-Hsien Wu ◽  
Che-Hsin Lee
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Lung Metastases ◽  
Macrophage Polarization ◽  
Interleukin 1 ◽  
Mammalian Target Of Rapamycin ◽  
High Mobility ◽  
Treated Group ◽  
Mesenchymal Transition ◽  
Oxide Synthase

Targeting metastasis is a vital strategy to improve the clinical outcome of cancer patients, specifically in cases with high-grade malignancies. Here, we employed a Salmonella-based treatment to address metastasis. The potential of Salmonella as an anticancer agent has been extensively studied; however, the mechanism through which it affects metastasis remains unclear. This study found that the epithelial-to-mesenchymal transition (EMT) inducer SNAI1 was markedly reduced in Salmonella-treated melanoma cells, as revealed by immunoblotting. Furthermore, wound healing and transwell assays showed a reduced in vitro cell migration following Salmonella treatment. Transfection experiments confirmed that Salmonella acted against metastasis by suppressing protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, which in turn inhibited SNAI1 expression. Since it is known that metastasis is also influenced by inflammation, we partly characterized the immune infiltrates in melanoma as affected by Salmonella treatment. We found through tumor-macrophage co-culture that Salmonella treatment increased high mobility group box 1 (HMGB1) secretion in tumors to coax the polarization of macrophages in favor of an M1-like phenotype, as shown by increased inducible nitric oxide synthase (iNOS) expression and Interleukin 1 Beta (IL-1β) secretion. Data from our animal study corroborated the in vitro findings, wherein the Salmonella-treated group obtained the lowest lung metastases, longer survival, and increased iNOS-expressing immune infiltrates.

scholarly journals From Beyond the Pale to the Pale Riders: The Emerging Association of Bacteria with Oral Cancer

2020 ◽  
Vol 99 (6) ◽  
pp. 604-612 ◽  
Author(s):  
Z.R. Fitzsimonds ◽  
C.J. Rodriguez-Hernandez ◽  
J. Bagaitkar ◽  
R.J. Lamont
Keyword(s):  
Oral Cancer ◽  
Epithelial Cells ◽  
Periodontal Disease ◽  
Bacterial Communities ◽  
Epithelial To Mesenchymal Transition ◽  
Driver Mutations ◽  
Oral Streptococci ◽  
Periodontal Pathogens ◽  
Mesenchymal Transition

Oral cancer, predominantly oral squamous cell carcinoma (OSCC), is the eighth-most common cancer worldwide, with a 5-y survival rate <50%. There are numerous risk factors for oral cancer, among which periodontal disease is gaining increasing recognition. The creation of a sustained dysbiotic proinflammatory environment by periodontal bacteria may serve to functionally link periodontal disease and oral cancer. Moreover, traditional periodontal pathogens, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, are among the species most frequently identified as being enriched in OSCC, and they possess a number of oncogenic properties. These organisms share the ability to attach and invade oral epithelial cells, and from there each undergoes its own unique molecular dialogue with the host epithelium, which ultimately converges on acquired phenotypes associated with cancer, including inhibition of apoptosis, increased proliferation, and activation of epithelial-to-mesenchymal transition leading to increased migration of epithelial cells. Additionally, emerging properties of structured bacterial communities may increase oncogenic potential, and consortia of P. gingivalis and F. nucleatum are synergistically pathogenic within in vivo oral cancer models. Interestingly, however, some species of oral streptococci can antagonize the phenotypes induced by P. gingivalis, indicating functionally specialized roles for bacteria in oncogenic communities. Transcriptomic data support the concept that functional, rather than compositional, properties of oral bacterial communities have more relevance to cancer development. Collectively, the evidence is consistent with a modified polymicrobial synergy and dysbiosis model for bacterial involvement in OSCC, with driver mutations generating a conducive microenvironment on the epithelial boundary, which becomes further dysbiotic by the synergistic action of bacterial communities.

Blocking the mTOR pathway: a drug discovery perspective

2011 ◽  
Vol 39 (2) ◽  
pp. 451-455 ◽  
Author(s):  
Carlos Garcia-Echeverria
Keyword(s):  
Drug Discovery ◽  
Cancer Patients ◽  
Cancer Biology ◽  
Human Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mechanisms Of Action ◽  
Mtor Pathway ◽  
Lipid Kinase ◽  
Phosphoinositide 3 Kinase

Substantial drug discovery efforts have been devoted, over the last few years, to identifying and developing mTOR (mammalian target of rapamycin) kinase modulators. This has resulted in a number of mTOR inhibitors with different mechanisms of action and/or distinct protein and lipid kinase selectivity profiles. As briefly reviewed in the present paper, these compounds have provided us with a better understanding of the roles of mTOR and other phosphoinositide 3-kinase/mTOR pathway components in human cancer biology, and a few of them have already demonstrated clinical benefit in cancer patients.

scholarly journals mTOR Signaling at the Crossroad between Metazoan Regeneration and Human Diseases

2020 ◽  
Vol 21 (8) ◽  
pp. 2718 ◽  
Author(s):  
Yasmine Lund-Ricard ◽  
Patrick Cormier ◽  
Julia Morales ◽  
Agnès Boutet
Keyword(s):  
Evolutionary Biology ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Human Diseases ◽  
Whole Body ◽  
Body Parts ◽  
Animal Kingdom ◽  
Structure Damage ◽  
Wide Range

A major challenge in medical research resides in controlling the molecular processes of tissue regeneration, as organ and structure damage are central to several human diseases. A survey of the literature reveals that mTOR (mechanistic/mammalian target of rapamycin) is involved in a wide range of regeneration mechanisms in the animal kingdom. More particularly, cellular processes such as growth, proliferation, and differentiation are controlled by mTOR. In addition, autophagy, stem cell maintenance or the newly described intermediate quiescence state, Galert, imply upstream monitoring by the mTOR pathway. In this review, we report the role of mTOR signaling in reparative regenerations in different tissues and body parts (e.g., axon, skeletal muscle, liver, epithelia, appendages, kidney, and whole-body), and highlight how the mTOR kinase can be viewed as a therapeutic target to boost organ repair. Studies in this area have focused on modulating the mTOR pathway in various animal models to elucidate its contribution to regeneration. The diversity of metazoan species used to identify the implication of this pathway might then serve applied medicine (in better understanding what is required for efficient treatments in human diseases) but also evolutionary biology. Indeed, species-specific differences in mTOR modulation can contain the keys to appreciate why certain regeneration processes have been lost or conserved in the animal kingdom.

The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 43-43
Author(s):  
Da Wang ◽  
Roland Chiu ◽  
John Theodorus Plukker ◽  
Robert P. Coppes
Keyword(s):  
Esophageal Cancer ◽  
Cell Lines ◽  
Mammalian Target Of Rapamycin ◽  
Neoadjuvant Chemoradiotherapy ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Biopsy ◽  
Sphere Formation ◽  
Dose Dependent

43 Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.

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