The IGF2/IGF1R/Nanog Signaling Pathway Regulates the Proliferation of Acute Myeloid Leukemia Stem Cells

Xu, Dandan; Wang, Ying; Zhou, Pengjun; Qin, Shurong; Zhang, Rong; Zhang, Yi; Xue, Xue; Wang, Jianping; Wang, Xia; Chen, Hongce; Wang, Xiao; Pan, Yuwei; Zhang, Li; Yan, Hai‐Xing; Liu, Qiuying; Liu, Zhong; Chen, Suhong; Wang, Yifei

doi:10.3389/fphar.2018.00687

Cited by 24 publications

(15 citation statements)

References 56 publications

(99 reference statements)

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“…IGF‐1 attracted our attention, as both IGF‐1 and IGF‐2 activate IGFR1. It has been reported that IGFR1‐mediated expression of Nanog promotes the formation of cancer stem cells of HCC and the proliferation of acute myeloid leukemia stem cells, linking to cancer invasion, metastasis, and drug resistance. Tenascin C encoded by TNC regulates cancer stemness by activate Notch signaling of cancer cells .…”

Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Chen

et al. 2019

Hepatol Commun

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Transforming growth factor β (TGFβ) induces hepatic stellate cell (HSC) differentiation into tumor-promoting myofibroblast, although underlying mechanism remains incompletely understood. Focal adhesion kinase (FAK) is activated in response to TGFβ stimulation, so it transmits TGFβ stimulus to extracellular signal-regulated kinase and P38 mitogenactivated protein kinase signaling. However, it is unknown whether FAK can, in return, modulate TGFβ receptors. In this study, we tested whether FAK phosphorylated TGFβ receptor 2 (TGFβR2) and regulated TGFβR2 intracellular trafficking in HSCs. The FAKY397F mutant and PF-573,228 were used to inhibit the kinase activity of FAK, the TGFβR2 protein level was quantitated by immunoblotting, and HSC differentiation into myofibroblast was assessed by expression of HSC activation markers, alpha-smooth muscle actin, fibronectin, or connective tissue growth factor. We found that targeting FAK kinase activity suppressed the TGFβR2 protein level, TGFβ1-induced mothers against decapentaplegic homolog phosphorylation, and myofibroblastic activation of HSCs. At the molecular and cellular level, active FAK (phosphorylated FAK at tyrosine 397) bound to TGFβR2 and kept TGFβR2 at the peripheral plasma membrane of HSCs, and it induced TGFβR2 phosphorylation at tyrosine 336. In contrast, targeting FAK or mutating Y336 to F on TGFβR2 led to lysosomal sorting and degradation of TGFβR2. Using RNA sequencing, we identified that the transcripts of 764 TGFβ target genes were influenced by FAK inhibition, and that through FAK, TGFβ1 stimulated HSCs to produce a panel of tumor-promoting factors, including extracellular matrix remodeling proteins, growth factors and cytokines, and immune checkpoint molecule PD-L1. Functionally, targeting FAK inhibited tumorpromoting effects of HSCs in vitro and in a tumor implantation mouse model. Conclusion: FAK targets TGFβR2 to the plasma membrane and protects TGFβR2 from lysosome-mediated degradation, thereby promoting TGFβ-mediated HSC activation. FAK is a target for suppressing HSC activation and the hepatic tumor microenvironment. (Hepatology Communications 2020;4:268-283).269 express α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF), markers of HSC activation, (4,5) and paracrine factors that promote liver metastatic growth. (6) Understanding how TGFβ signaling events are regulated, such as how TGFβ receptors distribute and traffic in HSCs, will help identify targets to inhibit HSC activation and the metastasis-promoting liver microenvironment.Focal adhesion kinase (FAK) is a 125-kDa nonreceptor tyrosine (Y) kinase. It consists of an N-terminal FERM domain, a middle kinase domain, and a C-terminal FAT domain. (7,8) Inactive FAK exists as an auto-inhibited monomer, and its autophosphorylation at Y397 creates a binding site for SH2 domain of Src, so that Src is recruited to induce phosphorylation of FAK at additional sites, leading to full activation of FAK kinase. (7,8) In addition, FAK functions as a protein scaffold for sign...

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Section: Discussionmentioning

confidence: 99%

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Chen

et al. 2019

Hepatol Commun

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“…Picropodophyllin (PPP; AXL1717) is a clinically utilized, selective, small molecule inhibitor of IGF-IR [29–33]. It has been shown to be effective in inhibiting various types of cancers including those of the gastrointestinal tract, nasopharynx, liver, lung, ovary, soft tissues, and hematopoietic system including NPM-ALK + T cell lymphoma [21, 34–46]. Recently, however, higher doses of PPP have been shown to induce bone marrow toxicity in some patients [30].…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma

George

Shi

et al. 2019

J Hematol Oncol

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Background Nucleophosmin-anaplastic lymphoma kinase-expressing (NPM-ALK + ) T cell lymphoma is an aggressive neoplasm. NPM-ALK, an oncogenic tyrosine kinase, plays a critical role in this lymphoma. Recently, selective ALK inhibitors have emerged as a first-line therapy for this neoplasm. Unfortunately, ALK inhibitors were hindered by emergence of resistance and relapse. We have previously demonstrated that type I insulin-like growth factor receptor (IGF-IR) is commonly expressed and activated in this lymphoma. In addition, IGF-IR and NPM-ALK are physically associated and reciprocally enhance their phosphorylation/activation. Herein, we tested the hypothesis that combined inhibition of IGF-IR and NPM-ALK could significantly improve the effects of inhibiting each kinase alone. Methods We used clinically utilized inhibitors of IGF-IR (picropodophyllin; PPP) and ALK (ASP3026) to assess the in vitro cellular effects of combined treatment versus treatment using a single agent. Moreover, we used a systemic NPM-ALK + T cell lymphoma mouse model to analyze the in vivo effects of PPP and ASP3026 alone or in combination. Results Our data show that combined treatment with PPP and ASP3026 decreased the viability, proliferation, and anchorage-independent colony formation, and increased apoptosis of NPM-ALK + T cell lymphoma cells in vitro. The in vitro effects of combined treatment were synergistic and significantly more pronounced than the effects of PPP or ASP3026 alone. Biochemically, simultaneous antagonism of IGF-IR and ALK induced more pronounced decrease in pIGF-IR Y1135/1136 , pNPM-ALK Y646 , and pSTAT3 Y705 levels than antagonizing IGF-IR or ALK alone. Moreover, combined targeting of IGF-IR and NPM-ALK decreased significantly systemic lymphoma tumor growth and improved mice survival in vivo. Consistent with the in vitro results, the in vivo effects of the combined therapy were more pronounced than the effects of targeting IGF-IR or ALK alone. Conclusions Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK + T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed. Electronic supplementary material The online version of this article (10.1186/s13045-019-0768-8) contains supplementary material, which is available to authorized users.

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“…Primary human AML cells express insulin and IGF receptors, 23 and a recent article described associations between pretreatment serum levels of various IGF binding proteins and between the serum fraction of bound IGF and a favorable prognosis with increased survival. 24 Systemic insulin/IGF levels thus seem important for the effect of insulin/IGF1 in the AML cell microenvironment, and experimental studies further suggest that both insulin 25,26 and IGF 27 have growth-enhancing and/or antiapoptotic effects in primary human AML cells. However, the heterogeneity of constitutive and insulin-induced PI3K-Akt-mTOR network phosphorylation in primary AML cells has not been addressed previously, and our present study shows that constitutive phosphorylation (at least partly IGF dependent) differs between patients, but exposure to insulin adds further heterogeneity.…”

Section: Discussionmentioning

confidence: 98%

Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells

Nepstad

Hatfield

Grønningsæter

et al. 2019

Sig Transduct Target Ther

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The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients. The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators. However, insulin effects on the pathway activation profile varied among patients, and increased phosphorylation in all mediators was observed only in a minority of patients; in other patients, insulin had divergent effects. Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation, transcriptional regulation, RNA metabolism, and cellular metabolism. Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors. PI3K, Akt, and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin, although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation. For Akt inhibition, the phosphorylation of upstream mediators was generally increased or unaltered. In contrast, mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation. In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.

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The IGF2/IGF1R/Nanog Signaling Pathway Regulates the Proliferation of Acute Myeloid Leukemia Stem Cells

Cited by 24 publications

References 56 publications

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Focal Adhesion Kinase Promotes Hepatic Stellate Cell Activation by Regulating Plasma Membrane Localization of TGFβ Receptor 2

Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK+ T-cell lymphoma

Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells

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