The Complexity of Targeting PI3K-Akt-mTOR Signalling in Human Acute Myeloid Leukaemia: The Importance of Leukemic Cell Heterogeneity, Neighbouring Mesenchymal Stem Cells and Immunocompetent Cells
Abstract
:1. Introduction
2. PI3K-Akt-mTOR Signalling
2.1. PI3K
2.2. Akt (Protein Kinase B)
2.3. mTOR
2.4. Pharmacological Targeting of the PI3K-Akt-mTOR Pathway
3. Direct Effects of PI3K-Akt-mTOR Inhibition on AML Cells: Patient Heterogeneity and Resistance to Treatment
3.1. Dysregulation of PI3K-Akt-mTOR in Human Malignancies—General Comments
3.2. PI3K-Akt-mTOR Targeting in Human AML
- 50%–80% of AML patients display Akt that is phosphorylated at T308, S473 or both. This upregulation has been detected not only in bulk AML cells but also in the more immature leukemic stem cells [36,37]. Several studies suggest that both overall and disease-free survival is shorter in patients with PI3K-Akt-mTOR pathway upregulation [36]. In contrast, constitutive activation of the upstream PI3K may represent a favourable prognostic parameter [40].
- The causes for activation of PI3K-Akt-mTOR signalling can be mutations in the FMS-like tyrosine kinase 3 (Flt3), proto-oncogene c-Kit (CD117) or K-Ras genes, overexpression of PI3K or PDK-1, low levels of protein phosphatase 2 (PP2A), autocrine or paracrine release of growth factors (e.g., IGF-1, platelet-derived growth factor/PDGF or the chemokine CXCL12), stromal/fibronectin-induced upregulation of integrin-linked kinase 1 (ILK1), or PTEN loss [36,37]. Activating mutations in PI3K or Akt, however, are uncommon also in AML [36].
- Patients are heterogeneous with regard to the effect of PI3K-Akt-mTOR inhibitors on AML cell proliferation; although an antiproliferative effect is observed for most patients, no effect or even growth enhancement is seen for a subset of patients [27]. This adverse effect is possibly associated with differences in cell cycle regulation.
- There seems to exist several escape mechanisms to inhibition of this pathway [1]. Firstly, induction of autophagy during treatment may represent a mechanism of resistance, and combination of PI3K-Akt-mTOR and autophagy inhibitors has therefore been suggested. Secondly, paradoxical Akt phosphorylation during treatment may induce expression and autophosphorylation of the receptors for insulin, IGF-1 and PDGF resulting in increased pathway activation. This feedback effect can be blocked by PDGFR/IGF-1R/Flt3 inhibition. Thirdly, activation of MAPK-interacting kinases can increase eukaryotic translation initiation factor E4 (eIF4E) phosphorylation and thereby trigger synthesis of pro-survival proteins. Finally, increased signalling of alternative pathways (e.g., ERK upregulation) can also be seen. These observations clearly illustrate the intracellular complexity of PI3K-Akt-mTOR inhibition.
- New mTOR inhibitors seem to target both TORC1 and TORC2, whereas the earlier inhibitors targeted mainly TORC1; the more recent inhibitors may thereby have a stronger effect [23].
- 5′ AMP-activated protein kinase (AMPK) is an inhibitor of mTORC1; directly through inhibition of raptor and indirectly through activation of the TSC1/TSC2 complex [41]. At starvation, AMPK initiates increased fatty acid oxidation and also autophagy, and AMPK activation/agonists have a cytotoxic effect in AML cells [25].
- The combination of conventional chemotherapy with PI3K-Akt-mTOR inhibitors seems to have an acceptable toxicity, but further clinical studies are needed to clarify whether there are additive or synergistic antileukemic effects [38].
4. PI3K-Akt-mTOR in MSCs
4.1. Identification, Differentiation and Function of Bone Marrow MSCs
4.2. MSC Contributions to Stem Cell Niches in the Bone Marrow
5. The AML-Supporting Effects of Mesenchymal Stem Cells: Contributions from Cell-Cell Contact and Distant Effects Mediated through the Local Cytokine Network
5.1. Regulation of MSC Differentiation Is More Than PI3K-Akt-mTOR—The Importance of BMP, Wnt and Hedgehog Signalling
5.2. The General Effect of PI3K-Akt-mTOR Signalling on MSC Differentiation
5.3. The Unique Membrane Molecule Profile of MSCs: Possible Molecular Mechanisms for Communication with Neighbouring Cells through Direct Cell-Cell Contact and via the Local Cytokine Network
5.4. The Functional Importance of PI3K-Akt-mTOR Signalling in MSCs: The Effects on MSC Differentiation Are Only a Part of a More Extensive and Complex Biological Impact
5.5. Cytokine-Mediated Communication between MSCs and the Neighbouring Bone Marrow Cells; a Part of the AML-Supporting Effects by the MSCs
6. Direct Effects of PI3K-Akt-mTOR Inhibition on Immunocompetent Cells and the Dual Function of Monocytes/Macrophages as Immunocompetent Cells and Members of the Stem Cell Niches
6.1. PI3K-Akt-mTOR, MSCs and Immunocompetent Cells; Regulation of Allogeneic and Autologous Antileukemic Immune Reactivity
6.2. The Role of AKT/mTOR as Regulators of Macrophage Metabolism and Cytokine Release
- Increased glycolysis in response to TLR stimulation can be mediated by Akt independent of mTORC1.
- 4E-BP1 and 6SK1 have important roles in controlling the synthesis of both cytokines as well as HIF-1α and IRF-7 that are necessary for the cytokine synthesis.
- Activation of sterol regulatory element-binding protein 1 (SRBP1) is important for synthesis of lipid mediators and cytokines, and also for activation of the pentose-phosphate pathway that is required for adequate respiratory burst.
- mTORC1 is critical for control of glutamine metabolism that again is a regulator of the hexosamine pathway and the processes securing sufficient succinate accumulation.
6.3. The Role of Akt/mTOR in Macrophage Polarization—The Importance for AML Cells and Immunoregulation
6.4. The Effect of Pharmacological Inhibition of Akt/mTOR in Macrophages
7. Summarizing Discussion
7.1. The Complexity of PI3K-Akt-mTOR Signalling—What Is the Optimal Molecular Target for Pathway Inhibition?
7.2. The Complexity and Heterogeneity of Human AML; the Consequences from PI3K-Akt-mTOR Inhibition in the Leukemic Cells with Regard to Communication with Neighbouring Cells May Differ among Patients
7.3. The Complex Effects of PI3K-Akt-mTOR Signalling in MSCs
7.4. The Complex Effects of PI3K-Akt-mTOR Signalling in Macrophages and the Role of Other Immunocompetent Cells
8. Final Conclusions
Acknowledgments
Conflicts of Interest
References
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Direct Inhibition of the PI3K-Akt-mTOR Pathway Members |
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PI3K inhibitors |
Pan-PI3K inhibitors: buparlisib, pilaralisib, pictilisib |
Isoform-specific inhibitors: alpelisib, tazelisib, CAL-101, GDC-0941 |
Others: MVP-BAG956 (PI3K-PDK1), resveratrol (PI3K/Akt) |
Dual PI3K-mTOR inhibitors |
NVP-BEZ235, LY3023414, GSK2126458 |
Akt inhibitors |
MK-2206, uprosertib, ipatasertib, AZD5363 |
mTORC1 inhibitors |
Sirolimus, everolimus, temsirolimus, ridaforolimus |
Dual mTORC1/2 inhibitors |
LNK128, AZD8055, MLN0138, CC-223 |
Indirect Inhibition—Activation of Pathway Inhibitors |
AMPK agonists: metformin, A-769662GSK621 |
PTEN activation: l-sercurinine |
Adhesion Molecules and Other Cell Surface Molecules Involved in Local Cell-Cell or Cell-Matrix Contact | ||
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CD90: Thy-1 | A cell surface glycoprotein and member of the immunoglobulin superfamily involved in cell adhesion and cell communication in numerous cell types, including stem cells. | |
CD29: Integrin β1 [48] | Integrins are heterodimeric proteins that mediate bidirectional communication across the cell membrane. They are made up of α and β subunits. At least 18 α and eight β subunits have been described. This protein is a β subunit. | |
CD31: PECAM-1 [55] | This is a cell surface protein; it can be a part of intercellular junctions and is probably involved in leukocyte migration and integrin activation. | |
CD44: HCAM [50] | This cell-surface glycoprotein is a receptor for hyaluronic acid and is involved in cell-cell interactions, cell adhesion and migration. It can also interact with other ligands, such as osteopontin, collagens, and matrix metalloproteinases (MMPs). | |
CD48a/e/f: Integrins α1/α5/α6 [48,52] | These integrins are members of the immunoglobulin-like receptor family; it does not have a transmembrane domain, however, but is held at the cell surface by a GPI anchor via a C-terminal domain which may be cleaved to yield a soluble form of the receptor. | |
CD54: ICAM-1 [97] | This cell surface glycoprotein binds to integrins of type CD11a /CD18, or CD11b/CD18. | |
CD56 NCAM [48] | This cell adhesion protein is a member of the immunoglobulin superfamily, and it is involved in cell-cell as well as cell-matrix interactions. | |
CD62L/P: L/P-selectin [55] | CD62P: This 140 kDa membrane protein is a calcium-dependent receptor that binds to sialylated forms of carbohydrate antigens. CD62L: This cell surface adhesion molecule can mediate binding of leucocytes. | |
CD106: VCAM-1 [98] | This member of the Ig superfamily is a cell surface sialoglycoprotein mediating cell-cell adhesion and signal transduction. | |
CD146: MCAM [98] | Probably acting as a cell adhesion molecule. | |
Cadherin-11/Cadherin-2 [48] | Cadherin-11 is a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. This cadherin seems to have a specific function in bone development. Cadherin-2 is a classical cadherin, i.e., a calcium-dependent cell adhesion molecule and glycoprotein. | |
Cell Surface Cytokine Receptors | ||
CD95: Endoglin RNG | A homodimeric transmembrane protein, it is a component of the transforming growth factor β (TGF-β) receptor complex | |
CD71: Transferrin receptor protein 1 [47] | This cell surface receptor is necessary for cellular iron uptake by the process of receptor-mediated endocytosis. | |
CD117: c-Kit [99] | This protein is the receptor for the stem cell factor (SCF). | |
CD135: Flt3 [55] | This receptor is activated by binding of the Flt3 ligand. | |
CD166: ALCAM [46] | This protein is a member of a subfamily of immunoglobulin receptors and is a CD6 receptor; it is implicated in cell migration. | |
CD271: LNGFR [96] | This is the nerve growth factor receptor. | |
CD349: Frizzled-9 [52] | Members of the ‘frizzled’ gene family encode transmembrane proteins that are receptors for Wnt signalling proteins. | |
CCR1/4/6/7/9/10 CXCR4/5/6 CX3CR1 [94,95,100] | These are all chemokine receptors that can bind a wide range of CCL and CXCL chemokines; mediators which are important regulators of cell trafficking, cell cycle progression and cell survival. | |
Enzymes | ||
CD73: ecto 5′ nucleotidase | A plasma membrane protein that catalyses the conversion of extracellular nucleotides to membrane-permeable nucleosides. | |
CD10: Neprilysin [96] | A glycoprotein that is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones | |
CD13: Alanine aminopeptidase [96] | A plasma membrane protein; the large extracellular carboxy-terminal domain contains a pentapeptide consensus sequence characteristic of members of the zinc-binding metalloproteinase superfamily. The enzyme was thought to be involved in the metabolism of regulatory peptides. | |
Thrombospondin [48] | This protein has several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 motif. | |
Additional MSC-Expressed Molecules | ||
CD157: Stromal cell antigen [95] | This glycosylphosphatidylinositol-anchored molecule can facilitate cell growth. | |
Nestin [52] | This protein is a member of the intermediate filament protein family. | |
Sox-2 [50] | This protein is a member of the SRY-related HMG-box (SOX) family of transcription factors required for stem-cell maintenance. | |
OCT-4 [50] | This transcription factor is important for stem cell pluripotency. |
Aging of MSCs: PI3K-Akt-mTOR Inhibition Maintains an Immature State |
BM MSCs show decreased self-renewal, differentiation and function with aging; inhibition of the PI3K-Akt-mTOR pathway preserves the immature state and prevents the development of the age-related phenotype [109]. Increased expression of the transcription factors NANOG and OCT-1 may be responsible for this. Furthermore, a comparison of BM MSCs for younger (<30 years of age) and elderly (>70 years of age) individuals showed increased expression of genes associated with mTOR signalling [123]. Studies of both murine and human BM MSCs have shown that miR-188 regulates the age-related switch between osteoblast and adipocyte differentiation, and miR-188 then targets rictor [116]. Animal studies have shown decreased BM levels of IGF-1 in aged rats; IGF-1 seems to stimulate osteoblastic MSC differentiation through activation of mTOR and aging of MSCs may thus be caused by decreased mTOR signalling [131]. |
Metabolic Regulation |
MSC proliferation is regulated by extracellular glucose levels; this effect is mediated through both the PKC-MAPK and PI3K-Akt-mTOR pathways [124]. Glycogen synthase kinase 3 β is a metabolic regulator; inactivation of this regulator can be caused by signalling through mTORC2 and Akt phosphorylation at S437 [104]. |
Differentiation of MSCs—General Effects |
Murine studies suggest that absence of mTORC1 causes reduced capacity of adipocyte differentiation, whereas absence of mTOCR2 causes reduced osteogenic differentiation capacity and accelerated adipogenesis [91,126]. mTORC2 regulates mechanically induced cytoskeletal reorganization (actin stress fibre development) and favours osteogenesis over adipogenesis [126]. The stemness marker CD49f identifies a subset with high proliferative ability and differentiation potential; downregulation of this marker (i.e., knockdown, tumour necrosis factor α, TNF-α, treatment) is associated with decreased differentiation and downregulation through TNF-α is mediated by mTOR [132]. |
Osteogenic Differentiation of MSCs |
IGF-1-induced growth enhancement and osteoblastic differentiation of MSCs is inhibited by mTORC1 inhibitor rapamycin; this IGF-1effect is seen for MSCs derived from different tissues including BM [106,131]. The osteogenic effect of erythropoietin is mediated through various intracellular pathways, including signalling through PI3K and mTOR [113,125]. There seems to be a time-dependent modulation of AMPK-Akt-mTOR signalling during osteogenic differentiation with early activation of AMPK/raptor and thereby mTOR/S6K1 inhibition, and later activation of Akt/mTOR [120]. Stat3 activation seems to be a negative regulator of osteogenic differentiation [115]. BMP-2 and -4 stimulate osteogenic differentiation; JAK2 signalling then mediates Stat3 tyrosine phosphorylation whereas serine phosphorylation is mediated through ERK1/2 and mTOR signalling. Stat3 knockdown accelerates and augments osteogenic differentiation. mTOR inhibitors can increase osteogenic differentiation [119], and studies in human BM MSCs suggest that osteopenia can be induced through PI3K-Akt-mTOR and activation of S6K1 [118]. However, the effects of the PI3K-Akt-mTOR pathway are complex and effects of pathway inhibitors are difficult to predict. Induction of osteogenic differentiation has not been detected in all experimental models, and a possible explanation is that the final effect of mTOR inhibitors depends on the experimental model and the biological context [2]. However, the dual PI3K/mTOR inhibitor BEZ235 strongly inhibited osteogenic differentiation in human MSCs [119]. |
Adipocytic Differentiation of MSCs |
Adipocytic differentiation is associated with downregulation of Notch gene expression; modulation of PTEN-PI3K-Akt-mTOR signalling seems important for this Notch effect [127]. Insulin, Akt and mTOR signalling is important in adipocyte differentiation and rapamycin can reduce the expression of most adipocyte markers [2]. mTOR is essential for adipocytes to sense nutrient availability and modulation of PPAR-γ activity that is an important regulator of the adipogenic gene expression program [2]. Differentiation of brown adipocytes requires signalling pathways distinct from white adipocytes; mTOR activity is involved in the initial steps but later inhibition through AMPK activation is also necessary [2]. |
Myogenic Differentiation |
A recent review concluded that several studies suggest that mTOR is indispensable for myogenesis, but the mechanisms behind this function are largely unknown [2]. |
Regulation of Autophagy and Senescence in MSCs |
Autophagy is the natural regulated mechanism that disassembles unnecessary or dysfunctional cellular components. Cellular senescence is the phenomenon by which normal diploid cells cease to divide, but they remain metabolically active and commonly adopt an immunogenic phenotype consisting of a pro-inflammatory secretome. These two processes seem to be regulated by overlapping mechanisms. AMPK is a positive regulator of autophagy in MSCs; autophagy can then be activated through the AMPK-mTOR pathway and protect BM MSCs from stress-induced apoptosis [133]. Animal studies suggest that senescent BM MSCs show upregulation of p53 and downregulation of mTOR. Knockdown of p53 then alleviates senescence, reduces autophagy and upregulates mTOR [134]. Human BM MSCs show downregulation of Notch gene expression during adipocyte differentiation; Notch inhibition will also enhance adipocyte differentiation and at the same time induce autophagy by acting on the PTEN-PI3K-Akt-mTOR pathway [127]. mTOR inhibition can also reverse the senescent phenotype of human MSCs [110]. Thus, the PI3K-Akt-mTOR pathway is involved in the regulation of senescence/autophagy/apoptosis in BM MSCs. |
Adaptation to the Hypoxic BM Microenvironment |
The BM microenvironment is hypoxic [105,107,111]; the hypoxia seems to causes upregulation of hypoxia-inducible factor 1α (HIF-1α) in primary human AML cells and increased constitutive release of several cytokines by the leukemic cells [112]. Hypoxia induces autophagy and eventually apoptosis in BM MSCs; at the same time hypoxia seems to activate AMPK-mTOR signalling and inhibition of mTOR will then further increase the hypoxia-induced apoptosis [134]. However, hypoxia stimulated by Toll-like receptor (TLR) ligation show decreased apoptosis in response to hypoxia and at the same time increased autophagy and activated AMPK-mTOR signalling [117]. Furthermore, downregulation of leptin will attenuate hypoxia-induced autophagy [128]. Finally, hypoxia also increases the levels of fatty acid synthetase in umbilical cord MSCs; increased signalling through HIF-1α-fatty acid synthase-mTORC1 then represents an important link between hypoxia-induced lipid metabolism and increased proliferation as well as migration of MSCs [114]. Thus, autophagy seems to protect MSCs against hypoxia-induced apoptosis; AMPK-mTOR signalling seems important for regulation of autophagy and thereby also for the adaptation of MSCs to a hypoxic BM microenvironment together with leptin and possibly p53 (see above). |
Communication between MSCs and Neighbouring Cells |
Fibroblasts: Fibroblasts can support AML cell proliferation; they also show constitutive release of leukaemia-supporting/angioregulatory cytokines and this release can be altered by PI3K/mTOR inhibition [76]. Conditioned medium from cultures of BM MSCs suppresses fibroblast proliferation; this effect is mediated mainly by TGF-β3 [130]. However, MSCs release a wide range of soluble mediators and other forms of TGF-β that signal through the same receptors [108]; probably, other cytokines/chemokines may also contribute to this effect. PI3K-Akt-mTOR signalling is a downstream effect to TGF-receptors, and this pathway is also important for fibroblast proliferation (both mTORC1 and mTORC2), adherence and release of extracellular matrix molecules [108,121,122,129]. Thus, PI3K-Akt-mTOR targeting may alter this crosstalk between MSCs and fibroblasts both through effects on MSCs and the fibroblasts. Osteoblasts: mTOR/S6K1 signalling is important for osteoblast responses to exogenous cytokines and for the regulation of osteoblast cytokine release [2], including cytokines that can support leukemogenesis and modulate other stromal cells including MSCs [2]. |
Soluble Mediators Released by MSCs |
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Interleukins |
IL-1α/β [47], IL-6 [55,136], IL-10 [139,140], IL-15 [141] |
Chemokines |
CCL2 [94,95], CCL3 [94], CCL4 [95], CCL5 [94,95], CCL7 [53], CCL20 [95], CCL26 [53], CXCL1 [53], CXCL2 [53], CXCL5 [53], CXCL8 [94,136], CXCL10 [53], CXCL11 [53], CXCL12 [94,95], CX3CL1 [95] |
Growth factors |
Ang-1 [94], VEGF [94,136], TGF-β [139,140,142], PDGF [50], bFGF [50], FGF7 [50], HGF [139,140,142], IGF-1 [45], EGF [45], G-CSF [55], M-CSF [55], GM-CSF [55], SCF [55], LIF [55], IFN-β [136] |
Other mediators |
PGE2 [139,140,142] |
Soluble Mediators Commonly Released by Various Malignant Cells |
IL-6 [93,143], Ang-1 [144], VEGF [144], TGF-β, BMP-4 [143], Wnt5α [144], Gremlin-1 [144], bFGF [143,144], HGF [143], IGF-I/II [143], EGF [144], CTGF [143], G-CSF [144], CCL5 [93,143], CXCL12 [93,143] |
T Cells |
|
NK Cells |
|
B Cells |
|
Dendritic Cells |
Media-TOR | M1/M2 Ratio | Comment | Reference |
---|---|---|---|
Akt1 | M1↑M2↓ | Akt is expressed as the three different isoform Akt1, Akt2 and Akt 3. These isoforms contributes differentially to differentiation of monocytes into the two main forms: M1: Reduced responsiveness to TLR ligands, reduced secretion of IL-1βα, IL-6 and TNF-α. M2: C/EBPβ seems important for M2 differentiation, Stat6 also seems to be involved together with miR-155. The Akt1 isoform facilitates differentiation into the M2 phenotype, and Akt2 downregulation upregulates C/EBPβ. Akt1 is important for Akt-mediated effects on ECs whereas Akt2 is important in insulin signalling. | [174] |
Akt2 | M1↓M2↑ | Akt2 induces differentiation in direction of the pro-inflammatory M1 phenotype. | [174,175] |
AMPKα1 | M1↓M2↑ | AMPK activation in macrophages results in results in polarization to the anti-inflammatory M2 phenotype. Exposure of macrophages to IL-10 causes AMPK activation, and AMPKα1 is then required for IL-10 activation of PI3K-Akt-mTORC1 and Stat3-mediated anti-inflammatory pathways regulating macrophage polarization. | [171] |
AMPKβ1 | M1↓M2↑ | Animal studies demonstrated that AMPKβ1 deficient macrophages are M1-activated, i.e., AMPK seems to differentiate macrophages towards an immunosuppressive M2 phenotype. | [170] |
PTEN | M1↓M2↑ | PTEN is important for the increased release of pro-inflammatory cytokines such as IL-6 by macrophages in response to TLR ligation, and deletion of PTEN then results in diminished inflammatory responses. Furthermore, macrophages isolated from such knockout mice express higher levels of M2 markers, produce lower TNF-α and higher IL-10 levels in response to TLR ligation. Such M2 macrophages also show enhanced Stat3- and Stat6-signalling together with diminished Stat1-signalling pathway activation in response to TLR4 stimulation. | [172,173] |
PDK1 | M1↑M2↓ | A major characteristic of mice with myeloid PDK1 knockout is increased tissue infiltration of macrophages with the M1 phenotype; the authors concluded that PDK1 regulates macrophage migration through inhibition of FOXO-1 induced CCR2 expression. | [190] |
Inpp5d | M2↑ | Inositol polyphosphate-5-phosphatase D. The expression of this protein is restricted to haematopoietic cells and it functions as a negative regulator of myeloid cell proliferation and survival. Deficient murine monocytes are more sensitive to IL4-induced induction of the M2 phenotype. | [191] |
TSC1 | M1↑M2↓ | Knockout of TSC1 in the myeloid lineage causes constitutive mTORC1 activation with downregulation of Akt signalling that is essential for resistance to M2 polarization and increased responsiveness to pro-inflammatory stimuli. Thus, the effect can at least partly be explained by increased mTORC1 activity with a negative feedback on Akt function. The TSC1 deficient cells show impaired migration and reduced expression of chemokine receptors, including CCR2 and CCR5, phagocytosis and reactive oxygen species production is increased and the effect of the knockdown is partially reversed by mTORC1 inhibitors. | [176,177,178] |
Raptor | M1↓M2↑ | Raptor deficiency reduced inflammatory gene expression in macrophages derived from several organs, including BM macrophages. This seems to be caused by attenuation of Akt inactivation and increased NFκB signalling. | [192] |
Rictor | M1↑M2↓ | Primary macrophages isolated from myeloid-specific rictor null mice exhibited an exaggerated response to TLRs ligands, and expressed high levels of M1 genes and lower levels of M2 markers. | [179] |
Hallmark | Drug | Cells | Effect | Reference |
---|---|---|---|---|
Cytokine Production | Sirolimus | THP-1 human AML monocytic cell line Normal human monocytes | Sirolimus reduced release of CCL2, CCL3, CCL5 and CXCL8 in both human and murine monocytes; CCL4 was in addition reduced in human cells. There was no effect on TNF-α release. | [183] |
Everolimus | C57BL/6 murine cells Normal human monocytes | While mTOR inhibition did not lead to any changes during starvation, everolimus significantly increased production of IL-6, CCL2, CCL5 and TNF-α and except for CCL2 this increase was inhibited by MAPK inhibition. | [184] | |
Rapamycin | Normal human monocytes tested in vivo and in vitro | Rapamycin induced apoptosis of M2- but not M1 polarized cells. M1 polarized: rapamycin reduced the release of CXCR4 and expression of CD206 and CD209; also reduced stem cell growth factor β, CCL4 and CCL13. M2 polarized: rapamycin increased expression of CD86, CCR7, IL-6 and TNF-α; reduced CD206, IL-10, VEGF and CCL18. Stimulation by LPS, Listeria Pam3Cys or flagellin; increased release of IL12p40 and IL-23, reduced TNF-α and IL-6. | [185] | |
Everolimus | Rat monocytes, in vivo studies | Histological examination of induced experimental neuritis showed that everolimus significantly (i) increased accumulation of M2 cells, spleen M2 cells were also increased; (ii) mRNA levels of INF-γ and IL-17 were reduced whereas they increased for TGF-β and IL-4; (iii) cytokine protein levels showed reduced IL-1α, IFN-γ and CCL5 but increased IL-10 levels. | [181] | |
Rapamycin | Human, in vitro | Rapamycin decreased IL-6 and IL-10 but did not affect TNF-α release after LPS exposure. | [186] | |
In vivo migration | Everolimus | In vivo and in vitro studies Monocytes | Everolimus reduced migration of macrophages to atherosclerotic plaque in the carotis wall; in vitro studies showed reduced migration towards CCL2, CXCL3, CXCL8, C5a and N-formylmethionyl-leucyl-phenylalanine. | [180] |
Foam cells formation | Everolimus | THP-1 foam cells | Decreased viability of foam cells, no effect on release of IL-1β, CXCL8, TNF-α but reduced release of CCL2; increase cellular clustering. | [182] |
Expression of TLRs | Everolimus | Normal human monocytes, in vitro studies | A significant increase in TLR expression by monocytes was seen in patients with drug eluting stents compared with bare metal stents. | [187] |
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Brenner, A.K.; Andersson Tvedt, T.H.; Bruserud, Ø. The Complexity of Targeting PI3K-Akt-mTOR Signalling in Human Acute Myeloid Leukaemia: The Importance of Leukemic Cell Heterogeneity, Neighbouring Mesenchymal Stem Cells and Immunocompetent Cells. Molecules 2016, 21, 1512. https://doi.org/10.3390/molecules21111512
Brenner AK, Andersson Tvedt TH, Bruserud Ø. The Complexity of Targeting PI3K-Akt-mTOR Signalling in Human Acute Myeloid Leukaemia: The Importance of Leukemic Cell Heterogeneity, Neighbouring Mesenchymal Stem Cells and Immunocompetent Cells. Molecules. 2016; 21(11):1512. https://doi.org/10.3390/molecules21111512
Chicago/Turabian StyleBrenner, Annette K., Tor Henrik Andersson Tvedt, and Øystein Bruserud. 2016. "The Complexity of Targeting PI3K-Akt-mTOR Signalling in Human Acute Myeloid Leukaemia: The Importance of Leukemic Cell Heterogeneity, Neighbouring Mesenchymal Stem Cells and Immunocompetent Cells" Molecules 21, no. 11: 1512. https://doi.org/10.3390/molecules21111512