Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo

Schulte, Alexander; Ewald, Florian; Spyra, Melanie; Smit, Daniel J; Jiang, Wei; Salamon, Johannes; Jücker, Manfred; Mautner, Victor‐Felix

doi:10.3390/ijms21041548

Cited by 15 publications

(11 citation statements)

References 48 publications

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“…In this work, we provide first evidence on a crucial role of PI3K/AKT/mTOR signaling in CTC-MCC-41 cells. The sensitivity towards the allosteric AKT inhibitor MK2206 and the synergistic effects on the proliferation by additional targeting mTOR using RAD001 in the colon CTC line provides a rationale for dual targeting the AKT and mTOR axis as postulated earlier [44][45][46][47][48]. The complexity of signaling pathway networks including the PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK pathway makes it difficult to choose the right treatment without triggering crosstalk [49].…”

Section: Discussionmentioning

confidence: 99%

High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors

Smit

Cayrefourcq

Haider

et al. 2020

Cells

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Circulating tumor cells (CTCs) are cells shed from the primary tumor into the bloodstream. While many studies on solid tumor cells exist, data on CTCs are scarce. The mortality of cancer is mostly associated with metastasis and recent research identified CTCs as initiators of metastasis. The PI3K/AKT/mTOR signaling pathway is an intracellular pathway that regulates essential functions including protein biosynthesis, cell growth, cell cycle control, survival and migration. Importantly, activating oncogenic mutations and amplifications in this pathway are frequently observed in a wide variety of cancer entities, underlining the significance of this signaling pathway. In this study, we analyzed the functional role of the PI3K/AKT/mTOR signaling pathway in the CTC-MCC-41 line, derived from a patient with metastatic colorectal cancer. One striking finding in our study was the strong sensitivity of this CTC line against AKT inhibition using MK2206 and mTOR inhibition using RAD001 within the nanomolar range. This suggests that therapies targeting AKT and mTOR could have been beneficial for the patient from which the CTC line was isolated. Additionally, a dual targeting approach of AKT/mTOR inside the PI3K/AKT/mTOR signaling pathway in the colorectal CTCs showed synergistic effects in vitro. Depending on the phenotypical behavior of CTC-MCC-41 in cell culture (adherent vs. suspension), we identified altered phosphorylation levels inside the PI3K/AKT/mTOR pathway. We observed a downregulation of the PI3K/AKT/mTOR signaling pathway, but not of the RAS/RAF/MAPK pathway, in CTCs growing in suspension in comparison to adherent CTCs. Our results highlight distinct functions of AKT isoforms in CTC-MCC-41 cells with respect to cell proliferation. Knockdown of AKT1 and AKT2 leads to significantly impaired proliferation of CTC-MCC-41 cells in vitro. Therefore, our data demonstrate that the PI3K/AKT/mTOR signaling pathway plays a key role in the proliferation of CTC-MCC-41.

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Section: Discussionmentioning

confidence: 99%

High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors

Smit

Cayrefourcq

Haider

et al. 2020

Cells

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“…Many mutations in the mTOR pathway leading to its hyperactivity have been identified in cancer [ 24 ]. Both loss of function mutations in the negative mTOR regulators such as phosphatase and tensin homolog (PTEN), tuberous sclerosis complex (TSC1/2), neurofibromatosis type 1 (NF1), liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11) and gain of function mutations in positive mTOR regulators such as AKT (also known as protein kinase B (PKB)) and phosphoinositide-3-kinase (PI3K) result in hyperactivity of mTOR signaling in a large number of malignant tumors [ 25 , 26 ]. All these demonstrate that mTOR plays a central role in the occurrence and progression of a variety of cancers.…”

Section: Mtor Pathwaymentioning

confidence: 99%

The Translational Regulation in mTOR Pathway

Yang

Piao

et al. 2022

Biomolecules

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The mechanistic/mammalian target of rapamycin (mTOR) plays a master role in cell proliferation and growth in response to insulin, amino acids, energy levels, and oxygen. mTOR can coordinate upstream signals with downstream effectors, including transcriptional and translational apparatuses to regulate fundamental cellular processes such as energy utilization, protein synthesis, autophagy, cell growth, and proliferation. Of the above, protein synthesis is highly energy-consuming; thus, mRNA translation is under the tight and immediate control of mTOR signaling. The translational regulation driven by mTOR signaling mainly relies on eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP), ribosomal protein S6 kinase (S6K), and its downstream players, which are significant in rapid cellular response to environmental change. mTOR signaling not only controls the general mRNA translation, but preferential mRNA translation as well. This means that mTOR signaling shows the stronger selectivity to particular target mRNAs. Some evidence has supported the contribution of 4E-BP and La-related proteins 1 (LARP1) to such translational regulation. In this review, we summarize the mTOR pathway and mainly focus on mTOR-mediated mRNA translational regulation. We introduce the major components of mTOR signaling and their functions in translational control in a general or particular manner, and describe how the specificity of regulation is coordinated. Furthermore, we summarize recent research progress and propose additional ideas for reference. Because the mTOR pathway is on the center of cell growth and metabolism, comprehensively understanding this pathway will contribute to the therapy of related diseases, including cancers, type 2 diabetes, obesity, and neurodegeneration.

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“…It is a classical signaling pathway for autophagy activation and the main gateway to autophagy ( 18 , 19 ). In particular, various studies have reported activation of the PI3K/AKT/mTOR signaling pathway in NF1 -related MPNSTs ( 35 , 36 ). Previous studies by Tan et al ( 20 ) and Li et al ( 13 ), combined with the present study, demonstrate that regulation of autophagy facilitates NF1 -mediated modulation of osteogenic differentiation of BMSCs via the PI3K/AKT/mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Autophagy is involved in neurofibromatosis type I gene‑modulated osteogenic differentiation in human bone mesenchymal stem cells

Zhu

Lin

et al. 2021

Exp Ther Med

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Neurofibromatosis type I (NF1) is an autosomal dominant genetic disease that is caused by mutations in the NF1 gene. Various studies have previously demonstrated that the mTOR complex 1 signaling pathway is essential for the NF1-modulated osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, the mTOR signaling pathway plays a notable role in autophagy. The present study hypothesized that NF1 could modulate the osteogenic differentiation of BMSCs by regulating the autophagic activities of BMSCs. In the present study, human BMSCs were cultured in an osteogenic induction medium. The expression of the NF1 gene was either knocked down or overexpressed by transfection with a specific small interfering RNA (siRNA) targeting NF1 or the pcDNA3.0 NF1-overexpression plasmid, respectively. Autophagic activities of BMSCs (Beclin-1, P62, LC3B I, and LC3B II) were determined using western blotting, electron microscopy, acridine orange (AO) staining and autophagic flux/lysosomal detection by fluorescence microscopy. In addition, the autophagy activator rapamycin (RAPA) and inhibitor 3-methyladenine (3-MA) were used to investigate the effects of autophagy on NF1-modulated osteogenic differentiation in BMSCs. Inhibiting NF1 with siRNA significantly decreased the expression levels of autophagy markers Beclin-1 and LC3B-II, in addition to osteogenic differentiation markers osterix, runt-related transcription factor 2 and alkaline phosphatase. By contrast, overexpressing NF1 with pcDNA3.0 significantly increased their levels. Transmission electron microscopy, AO staining and autophagic flux/lysosomal detection assays revealed that the extent of autophagosome formation was significantly decreased in the NF1-siRNA group but significantly increased in the NF1-pcDNA3.0 group when compared with the NC-siRNA and pcDNA3.0 groups, respectively. In addition, the activity of the PI3K/AKT/mTOR pathway [phosphorylated (p)-PI3K, p-AKT, p-mTOR and p-p70S6 kinase] was significantly upregulated in the NF1-siRNA group compared with the NC-siRNA group, and significantly inhibited in the NF1-pcDNA3.0 group, compared with the pcDNA3.0 group. The knockdown effects of NF1-siRNA on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy activator RAPA, while the overexpression effects of NF1-pcDNA3.0 on the autophagy and osteogenic differentiation of BMSCs were reversed by the autophagy inhibitor 3-MA. In conclusion, results from the present study suggest at the involvement of autophagy in the NF1-modulated osteogenic differentiation of BMSCs. Furthermore, NF1 may partially regulate the autophagic activity of BMSCs through the PI3K/AKT/mTOR signaling pathway.

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Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo

Cited by 15 publications

References 48 publications

High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors

High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors

The Translational Regulation in mTOR Pathway

Autophagy is involved in neurofibromatosis type I gene‑modulated osteogenic differentiation in human bone mesenchymal stem cells

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