mTOR: Role in cancer, metastasis and drug resistance

Murugan, Avaniyapuram Kannan

doi:10.1016/j.semcancer.2019.07.003

Cited by 332 publications

(290 citation statements)

References 217 publications

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“…While Szyniarowski et al (2011) did not find any effect on mTORC1 activity in breast cancer cell lines by analyzing the phosphorylation status its p70S6K [23], another study using chronic myeloid leukemia demonstrated suppressed autophagy by activating mTOR [22]. Furthermore, it was recently reported that mTOR mutations have essential implication in inducing resistance to the mTOR inhibitors preserving its activity [36], as observed in our study. One hypothesis for our findings would be that WNK2 could promote defects in the initial autophagy flux or autophagosome maturation [22,23].…”

Section: Discussionsupporting

confidence: 49%

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WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line

Alves

Costa

Martinho

et al. 2020

Cells

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Autophagy is a cell-survival pathway with dual role in tumorigenesis, promoting either tumor survival or tumor death. WNK2 gene, a member of the WNK (with no lysine (K)) subfamily, acts as a tumor suppressor gene in gliomas, regulating cell migration and invasion; however, its role in autophagy process is poorly explored. The WNK2-methylated human glioblastoma cell line A172 WT (wild type) was compared to transfected clones A172 EV (empty vector), and A172 WNK2 (WNK2 overexpression) for the evaluation of autophagy using an inhibitor (bafilomycin A1-baf A1) and an inducer (everolimus) of autophagic flux. Western blot and immunofluorescence approaches were used to monitor autophagic markers, LC3A/B and SQSTM1/p62. A172 WNK2 cells presented a significant decrease in LC3B and p62 protein levels, and in LC3A/B ratio when compared with control cells, after treatment with baf A1 + everolimus, suggesting that WNK2 overexpression inhibits the autophagic flux in gliomas. The mTOR pathway was also evaluated under the same conditions, and the observed results suggest that the inhibition of autophagy mediated by WNK2 occurs through a mTOR-independent pathway. In conclusion, the evaluation of the autophagic process demonstrated that WNK2 inhibits the autophagic flux in glioblastoma cell line.

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Section: Discussionsupporting

confidence: 49%

“…During autophagosome formation PI3K activity, an upstream element in the mTOR pathway, is required and when suppressed inhibits autophagic flux. In this sense, the mechanism used by WNK2 to inhibit autophagic flux would be similar to the 3-methyladedine autophagy inhibitor (3-MA) [36].…”

Section: Discussionmentioning

confidence: 99%

WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line

Alves

Costa

Martinho

et al. 2020

Cells

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“…Several interesting results from our study may promote further investigation into the functions and partners of miR-200s, push forward the clinical application of miR-200s and also provide us with more targets and strategies for therapy. Although not perfect, most of the findings from our results have been successfully confirmed by recent experimental literatures [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]. To better confirm the predictive power of our approach and understand the mechanisms underlying the initiation and progression of CRC, more large-scale and standard investigations are worth conducting.…”

Section: Discussionsupporting

confidence: 71%

“…The aberrant RAS signaling may cause carcinogenesis and targeting it may bring substantial improvement in clinical outcome in metastatic colorectal cancers [43]. It is well established that mTOR signaling, a critical protein in regulating cancer cells, takes part in varieties of fundamental biological activities containing cell death, autophagy, metabolic reprogramming, cell growth, and cell cycle [44]. HIF-1, a transcription factor with important part in response to low oxygen concentrations, or hypoxia, play significant roles in normal tissue development and function and cancer progression [45].…”

Section: Discussionmentioning

confidence: 99%

Integrated characterization and validation of the prognostic significance of microRNA-200s in colorectal cancer

Peng

Cheng

et al. 2020

Cancer Cell Int

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Background: Accumulating evidence has demonstrated that could serve as promising molecular biomarkers for cancer prognosis. Nevertheless, the associations between miR-200s expression and colorectal cancer (CRC) prognosis remain controversial. Methods:We applied two mainstream approaches combining meta-analysis and bioinformatics analysis to answer whether miR-200s were associated with the prognosis of CRC patients and why miR-200s could be used as prognostic biomarkers for CRC. Results:Consequently, low expression of miR-200s was associated with unfavorable overall survival (OS) in CRC patients (HR: 1.09; 95% CI 1.01-1.17; P = 0.025). According to the subgroup analysis, the prognostic role of miR-200s was more significant for tissue samples, large samples, American patients and miR-200a subgroups. Then the target genes of miR-200s were predicted and applied for functional enrichment analyses. The results showed that the target genes of miR-200s were mainly enriched into some vital ontology subjects such as regulation ability, key cell structures and binding function. Moreover, a series of important signaling pathways were identified, which were significantly linked with the initiation and progression of CRC. Additionally, a protein-protein interaction (PPI) network of miR-200s targets was constructed to screen hub genes and modules. The identified hub genes and modules were validated to be highly involved in the occurrence and development of CRC.Conclusions: Current evidences revealed that miR-200s could be promising biomarkers for CRC prognosis. However, the findings still need to be validated with more larger-scale prospective studies and biological experiments before miR-200s could be applied into clinical application.

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“…The Hh pathway is also highly conserved and crucial for the normal The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that regulates a variety of fundamental cellular processes including protein synthesis, growth, metabolism, aging, regeneration and autophagy, and plays important roles during the early stages of brain development. 119 According to the literature, the activation of the Pten-AKT-mTORC1 axis is necessary for MSI2-transformation of the intestinal epithelium. 120 In addition, activation of the PDK1-AKT axis downstream of Pten by Msi1 contributes to the observed increase in mTORC1 activity in the intestinal 121 via the activation of the PDK1-AKT axis, downstream of Pten.…”

Section: Hedgehog (Hh) Pathwaymentioning

confidence: 99%

Interplay between the RNA binding‐protein Musashi and developmental signaling pathways

Chagas

Baroni

Brassesco

et al. 2020

The Journal of Gene Medicine

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Musashi comprises an evolutionarily conserved family of RNA-binding proteins (RBP) that regulate cell fate decisions during embryonic development and play key roles in the maintenance of self-renewal and differentiation of stem cells and adult tissues.More recently, several studies have shown that any dysregulation of MSI1 and MSI2can lead to cellular dysfunctions promoting tissue instability and tumorigenesis.Moreover, several reports have characterized many molecular interactions between members of the Musashi family with ligands and receptors of the signaling pathways responsible for controlling normal embryonic development: Notch, Transforming Growth Factor Beta (TGF-β), Wingless (Wnt) and Hedgehog Signaling (Hh); all of which, when altered, are strongly associated with cancer onset and progression, especially in pediatric tumors. In this context, the present review aims to compile possible cross-talks between Musashi proteins and members of the above cited molecular pathways for which dysregulation plays important roles during carcinogenesis and may be modulated by these RBP. K E Y W O R D S cancer, Musashi

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mTOR: Role in cancer, metastasis and drug resistance

Cited by 332 publications

References 217 publications

WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line

WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line

Integrated characterization and validation of the prognostic significance of microRNA-200s in colorectal cancer

Interplay between the RNA binding‐protein Musashi and developmental signaling pathways

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