Cystitis-induced upregulation of tyrosine kinase (TrkA, TrkB) receptor expression and phosphorylation in rat micturition pathways

2002 ◽  
Vol 454 (2) ◽  
pp. 200-211 ◽  
Author(s):  
Li-Ya Qiao ◽  
Margaret A. Vizzard
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Expression ◽  
Trkb Receptor

scholarly journals Anlotinib Induced Apoptosis and Regulated the Chemosensitivity and Immune-Related Properties of Leukemia Stem Cells By Inhibiting JAK2-STAT3/5 Signaling

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-12
Author(s):  
Long Liu ◽  
Long Yue Jiang ◽  
Bing Xu
Keyword(s):  
Stem Cells ◽  
Tyrosine Kinase ◽  
Immune Evasion ◽  
Tyrosine Kinases ◽  
Receptor Expression ◽  
The Self ◽  
Leukemia Stem Cells ◽  
Self Renewal ◽  
Stat Signaling ◽  
Apoptotic Proteins

Acute myeloid leukemia (AML) is derived from small populations of leukemia stem cells (LSCs) characterized by the self-renewal and chemoresistant properties. Residual LSCs after chemotherapy remain as the critical barriers to cure. Clearance of LSCs might rationally lead to an improvement of clinical outcome. Recently studies showed that JAK/STAT signaling play an important role in the self-renewal of AML-LSCs due to increased growth factor (GF) receptor expression such as c-kit, FLT3, CD123 and altered GF signaling by activating tyrosine kinases. Therefore, targeting such tyrosine kinases might be a strategy to eliminate LSCs. Anlotinib displayed its anti-tumor activity in lung cancer by targeting tyrosine kinase of VEGFR, FGFR, PDGFR and c-kit. However, whether anlotinib could inhibit the GF receptor-related tyrosine kinase overactivation and its downstream JAK-STAT signaling, and subsequently kill LSCs or regulate LSCs biology remains largely unknown. To explore whether anlotinib could exert effective ani-LSCs activity, we treated LSC like cell lines (CD34+CD38-KG-1 and Kasumi-1) with anlotinib, and found anlotinib could effectively induce apoptosis of LSC-like cells in a dose- and time-dependent manner. Similar results were observed in primary CD34+CD38-AML LSCs; notably, anlotinib did not significantly kill normal CD34+ cells in vitro. Additionally, the anti-LSC activity of anlotinib was further confirmed in the xenograft mouse model by injection of Kasumi cells (LSC-like cell line) into irradiated female BALB/c nude mice. To determine whether anlotinib could inhibit the over activation of the GF receptor-related tyrosine kinase, we performed western blot at 12h after anlotinib treatment when LSC-like cells did not showed significant apoptosis. As a result, anlotinib inhibit c-kit phosphorylation and JAK2 activation. Intriguingly, unlike JAK2 inhibitors, anlotinib could not only the inhibit phosphorylation of STAT3 and STAT5 but also downregulate their expression. Chemoresistance and immune evasion were the key features of LSCs, JAK2-STAT3/5 signaling was reported to involved in chemoresistance by upregulating anti-apoptotic proteins such as Bcl-2 ,Mcl-1 and also involved in immune escape by inducing immune suppressive molecules such as PD-L1 ,TGF-β.Thus we evaluated Bcl-2 expression and found a significant decrease in LSC-likes cells after anlotinib treatment. Similarly, PD-L1 and TGF-β were also significantly downregulated after anlotinib treatment. In conclusion, anlotinib not only displayed the effective anti-LSCs activity but also might regulate the chemoresistance and immune evasion of LSC by downregulating the anti-apoptotic proteins and suppressive molecules such as PD-L1, TGF-β respectively. Consequently, anlotinib might has the potential to contribute to a deeper clearance of LSCs by combining with chemotherapy or immunotherapy. Disclosures No relevant conflicts of interest to declare.

Statin Treatment Prevents FLT3 Glycosylation and Overcomes Resistance to FLT3 Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1421-1421
Author(s):  
Allen Williams ◽  
Li Li ◽  
Bao Nguyen ◽  
Patrick Brown ◽  
Mark J. Levis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Drug Binding ◽  
Receptor Expression ◽  
Hematopoietic Stem ◽  
Clinical Resistance ◽  
Surface Localization

Abstract Abstract 1421 FLT3 is a receptor tyrosine kinase that is expressed on hematopoietic stem and progenitor cells where it functions in cell differentiation, survival and proliferation. It is also one of the most frequently mutated genes in acute myeloid leukemia (AML), and has thus become a target for modulation by the use of FLT3 tyrosine kinase inhibitors (TKI). Unfortunately, clinical resistance emanating via several different mechanisms has limited the potential benefit of FLT3 TKI. Some of these include FLT3 mutations that reduce drug binding, elevated FLT3 ligand (FL) levels that shift the dose-response curve and activation of parallel signaling pathways. These all pose major challenges to TKI effectiveness that must be overcome to improve patient outcomes. Since FLT3 is dependent upon N-linked glycosylation for its maturation and surface localization, we sought to determine whether statins might disrupt FLT3 signaling. Statins inhibit the mevalonate pathway and reduce levels of all ensuing end-products including dolichol, which transfers preassembled oligosaccharides onto nascent polypeptides. Here, we demonstrate by Western blotting that statins can indeed prevent complex FLT3 glycosylation, thus leading to loss of surface receptor expression. Immunofluorescence microscopy confirms a reduction in surface localization and a concomitant increase in intracellular FLT3/ITD accumulation. Interestingly, this aberrant localization was associated with increased STAT5 activation while inhibiting both MAP kinase and AKT phosphorylation. We have extended our previous findings that statins are cytotoxic to mutant FLT3 expressing cell lines to examine whether they are also able to overcome the resistance mechanisms discussed above. We show that the following mechanisms of resistance could be circumvented by fluvastatin. First, stimulation of BaF3 FLT3/ITD cells with exogenous FL at physiologic concentrations induces a three-fold increase in the IC50 for inhibition of phosphorylated FLT3/ITD by the FLT3 TKI lestaurtinib. Pretreatment with fluvastatin for 24 h eliminated surface FLT3/ITD: FL interactions and restored the potency of lestaurtinib. Secondly, resistance to another clinical FLT3 TKI, sorafenib, caused by the FLT3/ITD N676K or D835Y mutations increased the IC50 from 5 nM for BaF3/ITD cells to 30 nM and >50 nM, respectively. In contrast, both of these mutants remained just as sensitive to treatment with fluvastatin as were the BaF3/ITD cells (approx. IC50 of 0.2 μM). A third mechanism of resistance that can be circumvented by fluvastatin is the over expression and/or activation of alternative pathways that can compensate for inhibited FLT3. A model of this is rescue of BaF3 FLT3/ITD cell lines from FLT3 TKI-mediated cytotoxicity by stimulation with IL-3. When this cell line is stimulated with IL-3, fluvastatin is able to inhibit activation of STAT5, AKT and MAP kinase caused by the IL-3 receptor, as well as FLT3/ITD signaling, leading to cell death. Fluvastatin was also effective in other cell lines expressing constitutively activated FLT3 (Molm-14, MV4;11, HB1119 and SEM-K2 cells) and in other cell lines in which glycosylated transmembrane receptors drive proliferation (mutant c-Kit in Kasumi cells) but not in cells that rely upon intracellular kinases (BCR-ABL in K562 cells). Importantly, fluvastatin also reduced FLT3 glycosylation in and was cytotoxic to primary AML patient samples harboring FLT3/ITD mutations at therapeutically achievable concentrations (1 μM). Finally, fluvastatin reduced engraftment of BaF3 FLT3/ITD cells transplanted in syngeneic Balb/c mice and prolonged their survival. These results demonstrate that statins, a class of drugs already FDA approved, might be useful, either alone or in combination with a FLT3 TKI, in the management of FLT3 AML cases including those resistant to FLT3 TKI. Disclosures: Levis: Ambit Biosciences, Inc: Consultancy.

Tyrosine Kinase FLT3 and C-KIT Receptor Expression in Patients with Myelodysplastic Syndromes – A Preliminary Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4620-4620
Author(s):  
Emília Cortesão ◽  
Ana Cristina Goncalves ◽  
Isabel Sousa ◽  
Carlos Moucho ◽  
Luís Carlos Rito ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Gene Silencing ◽  
Receptor Tyrosine Kinase ◽  
Myelodysplastic Syndromes ◽  
Receptor Expression ◽  
Aberrant Methylation ◽  
Hematopoietic Stem ◽  
Preliminary Results ◽  
Flt3 Mutations

Abstract Abstract 4620 Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dyshematopoiesis and high susceptibility to acute myeloid leukemia. Deregulated epigenetic mechanisms are likely involved in the pathogenesis of MDS. Gene silencing through aberrant CpG island methylation is the most extensively analyzed epigenetic event in human tumorigenesis and has huge diagnostic and prognostic potential. Aberrant methylation of gene promoter region is responsible for inappropriate gene silencing, and it has been associated to initiation and progression of cancer. However, in the MDS disease process, more and more gene dysfunction has been related with the pathogenesis. FLT3 and c-KIT are important members of the receptor tyrosine kinase family that are overexpress or dysexpress in many malignant hematologic diseases. However, little is known about the distribution and the role of these proteins in MDS. The study is to investigate the role of receptor tyrosine kinase FLT3 and c-KIT expression in patients with myelodysplastic syndromes (MDS) and their clinical implication. We have at moment examined c-kit protein (CD117) expression by flow cytometry, in CD34 bone marrow cells collected at diagnosis of 12 patients with de novo MDS and 5 non-neoplastic patients (controls). FLT3 mutations, in particular Internal Tandem Duplications (ITD) and the D835 mutation were analysed by PCR-RFLP. The median age was 72 years (22–89), gender M/F=5/7, WHO subtypes: RCMD (n=6), RA (n=3), RARS (n=1), AREB-2 (n=1), CMML (n=1) and IPSS: low (n=6), intermediate-1 (n=5) and intermediate-2 (n=1). None of the patients evolved to acute leukemia, with a median follow up of 24 months (7–74). Our preliminary results show an increase in c-KIT expression in CD34 positive cells in MDS patients as compared with controls. However, the percentage of c-KIT protein expressing cells was also higher than in the controls in particular in CD34 negative cells. There was a correlation of the c-kIT protein expression with the CD34 antigen of the cells. Expression is correlated with the WHO MDS classification and with IPSS, being highest in RAEB-2 and INT2 MDS prognostic group. These results suggest that the elevated c-KIT expression could maintain the affected clone in MDS. Besides that we didn't find any FLT3 mutations in our population However further data and refinement of data analysis are needed to confirm our results and to predict clinical outcomes. The preliminary results suggest that c-KIT expression could be helpful to the pathogenesis and prognosis prediction of MDS patients. Disclosures: No relevant conflicts of interest to declare.

Tyrosine kinase receptor expression in thymomas

2004 ◽  
Vol 130 (4) ◽  
pp. 222-224 ◽  
Author(s):  
John D. Henley ◽  
Oscar W. Cummings ◽  
Patrick J. Loehrer, Sr.
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Expression ◽  
Tyrosine Kinase Receptor

scholarly journals Tyrosine Kinase Receptor Expression in Canine Liposarcoma

2016 ◽  
Vol 154 (1) ◽  
pp. 111
Author(s):  
G. Avallone ◽  
V. Pellegrino ◽  
P. Roccabianca ◽  
E. Lepri ◽  
L. Crippa ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Expression ◽  
Tyrosine Kinase Receptor

scholarly journals Tyrosine Kinase Receptor Expression in Canine Liposarcoma

2016 ◽  
Vol 54 (2) ◽  
pp. 212-217 ◽  
Author(s):  
G. Avallone ◽  
V. Pellegrino ◽  
P. Roccabianca ◽  
E. Lepri ◽  
L. Crippa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Mitotic Count ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Proliferation Index ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth

The expression of tyrosine kinase receptors is attracting major interest in human and veterinary oncological pathology because of their role as targets for adjuvant therapies. Little is known about tyrosine kinase receptor (TKR) expression in canine liposarcoma (LP), a soft tissue sarcoma. The aim of this study was to evaluate the immunohistochemical expression of the TKRs fibroblast growth factor receptor 1 (FGFR1) and platelet-derived growth factor receptor–β (PDGFRβ); their ligands, fibroblast growth factor 2 (FGF2) and platelet-derived growth factor B (PDGFB); and c-kit in canine LP. Immunohistochemical labeling was categorized as high or low expression and compared with the mitotic count and MIB-1–based proliferation index. Fifty canine LPs were examined, classified, and graded. Fourteen cases were classified as well differentiated, 7 as myxoid, 25 as pleomorphic, and 4 as dedifferentiated. Seventeen cases were grade 1, 26 were grade 2, and 7 were grade 3. A high expression of FGF2, FGFR1, PDGFB, and PDGFRβ was identified in 62% (31/50), 68% (34/50), 81.6% (40/49), and 70.8% (34/48) of the cases, respectively. c-kit was expressed in 12.5% (6/48) of the cases. Mitotic count negatively correlated with FGF2 ( R = –0.41; P < .01), being lower in cases with high FGF2 expression, and positively correlated with PDGFRβ ( R = 0.33; P < .01), being higher in cases with high PDGFRβ expression. No other statistically significant correlations were identified. These results suggest that the PDGFRβ-mediated pathway may have a role in the progression of canine LP and may thus represent a promising target for adjuvant cancer therapies.

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