mTOR Signaling Pathway and mTOR Inhibitors in Cancer Therapy

Gómez-Pinillos, Alejandro; Ferrari, Anna C.

doi:10.1016/j.hoc.2012.02.014

Cited by 108 publications

(106 citation statements)

References 130 publications

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“…We next analyzed mTOR signaling in keratinocytes. As shown in Figure 2A, phosphorylation ("p-") of mTORC1 substrates, including S6K1 and 4EBP1 [9,10,13], were significantly increased in keloid keratinocytes (compared to normal keratinocytes). Meanwhile, p-AKT (at Ser-473), an indicator of mTORC2 activation [14,15], was also higher in keloid keratinocytes (Figure 2A).…”

Section: Enhanced Cell Proliferation and Migration In Keloid Keratinomentioning

confidence: 91%

“…Signaling by mTOR promotes cell proliferation and migration in a positive manner [9,10]. The active form of mTOR (phospho-mTOR) is over-expressed in keloid [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…The active form of mTOR (phospho-mTOR) is over-expressed in keloid [6,7]. At least two multiple-protein mTOR complexes exist, including the traditional mTOR complex 1 (mTORC1), and the more recently discovered mTOR complex 2 (mTORC2) [9,10]. Composed of mTOR, Raptor and PRAS40, mTORC1 is rapamycin sensitive [11,12] and phosphorylates its target proteins, including p70S6K1 (S6K1) and eIF4E-binding protein 1 (4EBP1), to promote cell proliferation and migration [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

Liu

Wang

et al. 2018

Oncotarget

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Keloid is a dermal proliferative disorder characterized by the excessive keratinocyte proliferation and migration. mTOR over-activation is involved in the process. Here, we show that both mTOR complex 1 (mTORC1) and mTORC2 were hyper-activated in keloid-derived primary keratinocytes. OSI-027, an mTOR kinase inhibitor, potently inhibited proliferation and migration of keloid keratinocytes. OSI-027 disrupted the assembly of mTORC1 (mTOR-Raptor) and mTORC2 (mTOR-RictormLST8). Further, OSI-027 completely blocked the phosphorylations of the mTORC1 substrates (S6K1, S6 and 4EBP1) and the mTORC2 substrate (AKT, at Ser-473). OSI-027 was potent than rapamycin in inhibiting keloid keratinocytes. Moreover, restoring mTORC1 activation by the introduction of the constitutively active S6K1 only partly alleviated OSI-027-induced suppression on keloid keratinocytes. Notably, mTOR2 inhibition by Rictor siRNA also inhibited keloid keratinocyte proliferation and migration, although less efficiently than OSI-027. Together, concurrent targeting of mTORC1/2 by OSI-027 potently inhibits keloid keratinocyte proliferation and migration.www.impactjournals.com/oncotarget/ Vol.9, (No.1), Supplement 1, pp: s147-s154

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Section: Enhanced Cell Proliferation and Migration In Keloid Keratinomentioning

confidence: 91%

“…Signaling by mTOR promotes cell proliferation and migration in a positive manner [9,10]. The active form of mTOR (phospho-mTOR) is over-expressed in keloid [6,7].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

Liu

Wang

et al. 2018

Oncotarget

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“…23,24). Various mTOR inhibitors have been used in trials for cancer therapeutic (25,26). DEP domain-containing mTOR-interacting protein (DEPTOR), as a naturally occurring inhibitor of mTOR, usually acts as a tumor suppressor by blocking the activation of mTOR to inhibit cell proliferation, invasion, and survival effect of AKT (27,28).…”

Section: Introductionmentioning

confidence: 99%

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Zhou

Guo

et al. 2016

Molecular Cancer Research

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The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTORinteracting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1a, and bTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth.Implications: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression.

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“…This pathway also promotes tumor survival after radiation-induced DNA damage [12] . Dysregulation of this pathway is frequently observed in GBM and occurs via multiple mechanisms, including mutation of the PIK3CA gene [13] , deregulation of mTOR complexes [14] , and loss or mutation of the phosphatase and tensin homolog [15] . Inhibition of this cascade can enhance radiosensitivity of the tumor cells without affecting the normal cells, which is an attractive concept for improving therapeutic outcomes [16] .…”

Section: Introductionmentioning

confidence: 99%

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

et al. 2013

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Aim: NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor and shows dramatic effects on gliomas. The aim of this study was to investigate the effects of NVP-BEZ235 on the radiosensitivity and autophagy of glioma stem cells (GSCs) in vitro. Methods: Human GSCs (SU-2) were tested. The cell viability and survival from ionizing radiation (IR) were evaluated using MTT and clonogenic survival assay, respectively. Immunofluorescence assays were used to identify the formation of autophagosomes. The apoptotic cells were quantified with annexin V-FITC/PI staining and flow cytometry, and observed using Hoechst 33258 staining and fluorescence microscope. Western blot analysis was used to analyze the expression levels of proteins. Cell cycle status was determined by measuring DNA content after staining with PI. DNA repair in the cells was assessed using a comet assay. Results: Treatment of SU-2 cells with NVP-BEZ235 (10-320 nmol/L) alone suppressed the cell growth in a concentration-dependent manner. A low concentration of NVP-BEZ235 (10 nmol/L) significantly increased the radiation sensitivity of SU-2 cells, which could be blocked by co-treatment with 3-MA (50 µmol/L). In NVP-BEZ235-treated SU-2 cells, more punctate patterns of microtubule-associated protein LC3 immunoreactivity was observed, and the level of membrane-bound LC3-II was significantly increased. A combination of IR with NVP-BEZ235 significantly increased the apoptosis of SU-2 cells, as shown in the increased levels of BID, Bax, and active caspase-3, and decreased level of Bcl-2. Furthermore, the combination of IR with NVP-BEZ235 led to G 1 cell cycle arrest. Moreover, NVP-BEZ235 significantly attenuated the repair of IR-induced DNA damage as reflected by the tail length of the comet. Conclusion: NVP-BEZ235 increases the radiosensitivity of GSCs in vitro by activating autophagy that is associated with synergistic increase of apoptosis and cell-cycle arrest and decrease of DNA repair capacity.

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mTOR Signaling Pathway and mTOR Inhibitors in Cancer Therapy

Cited by 108 publications

References 130 publications

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

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