scholarly journals LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Amin Huang ◽  
Peiting Zeng ◽  
Yinguang Li ◽  
Wenhua Lu ◽  
Yaoming Lai
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Response Duration ◽  
Akt Signaling ◽  
Clinical Activity ◽  
Akt Signaling Pathway ◽  
Atp Production ◽  
Pi3k Inhibitor Ly294002

Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.

scholarly journals Downregulation of cAMP-Dependent Protein Kinase Inhibitor-b Promotes Preeclampsia by Decreasing Phosphorylated Akt

2020 ◽  
Vol 28 (1) ◽  
pp. 178-185
Author(s):  
Chunfeng Liu ◽  
Hao Wang ◽  
Mo Yang ◽  
Yiheng Liang ◽  
Li Jiang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Matrix Metalloproteinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Dependent Protein Kinase ◽  
Phosphorylated Akt ◽  
Dependent Protein

AbstractPreeclampsia is a multi-system disease that is unique to human pregnancy. Impaired extravillous trophoblast migration and invasion accompanied by poor spiral vascular remodeling is thought to be the initial reason. This study investigated cAMP-dependent protein kinase inhibitor-b(PKIB) expression in placentas and its involvement in the pathogenesis of PE. We used immunohistochemistry and western blotting to calculate PKIB levels in the placentas. Then we knocked down PKIB by siRNA and used real-time cell analysis to assess the invasion and migration ability of trophoblasts. Tube formation assay and spheroid sprouting assay were utilized to identify the ability to form vessels of trophoblasts. At last, western blotting was used to demonstrate the level of phosphorylated Akt, as well as downstream-related genes of Akt signaling pathway in trophoblasts. We first found that PKIB expression level was lower in the PE placentas than in the normal placentas. In addition, we found that downregulation of PKIB can inhibit the migration, invasion, and the ability to form vessels of HTR8/SVneo cells. Downregulation of PKIB leaded to a decrease in phosphorylated Akt, as well as downstream proteins such as matrix metalloproteinase 2, matrix metalloproteinase 9, and glycogen synthase kinase 3β, which are related to migration and invasion. Our study revealed that the downregulation of PKIB expression resulted in decreased migration, invasion, and vessel formation ability by regulating Akt signaling pathway in placental trophoblasts in PE.

scholarly journals The Antagonistic Effect of Glutamine on Zearalenone-Induced Apoptosis via PI3K/Akt Signaling Pathway in IPEC-J2 Cells

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 891
Author(s):  
Tianhu Wang ◽  
Jingjing Wang ◽  
Tong Zhang ◽  
Aixin Gu ◽  
Jianping Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Signaling Pathway ◽  
Nuclear Fission ◽  
Akt Signaling ◽  
Antagonistic Effect ◽  
Protective Effects ◽  
Akt Signaling Pathway ◽  
Pi3k Inhibitor Ly294002 ◽  
Apoptotic Genes ◽  
Induced Apoptosis

Zearalenone (ZEN) is a non-steroidal estrogen mycotoxin produced by Fusarium fungi, which inevitably exists in human and animal food or feed. Previous studies indicated that apoptosis seems to be a key determinant of ZEN-induced toxicity. This experiment aimed to investigate the protective effects of Glutamine (Gln) on ZEN-induced cytotoxicity in IPEC-J2 cells. The experimental results showed that Gln was able to alleviate the decline of cell viability and reduce the production of reactive oxygen species and calcium (Ca2+) induced by ZEN. Meanwhile, the mRNA expression of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, and catalase was up-regulated after Gln addition. Subsequently, Gln supplementation resulted in the nuclear fission and Bad-fluorescence distribution of apoptotic cells were weakened, and the mRNA expression and protein expression of pro-apoptotic genes and apoptotic rates were significantly reduced. Moreover, ZEN reduced the phosphorylation Akt, decreased the expression of Bcl-2, and increased the expression of Bax. Gln alleviated the above changes induced by ZEN and the antagonistic effects of Gln were disturbed by PI3K inhibitor (LY294002). To conclude, this study revealed that Gln exhibited significant protective effects on ZEN-induced apoptosis, and this effect may be attributed to the PI3K/Akt signaling pathway.

scholarly journals CNTN-1 promotes docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer

2021 ◽  
Vol 17 (1) ◽  
pp. 152-165 ◽  
Author(s):  
Binshen Chen ◽  
Yiming Zhang ◽  
Chaoming Li ◽  
Peng Xu ◽  
Yubo Gao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Cell Counting ◽  
Multi Drug Resistance ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition

IntroductionTherapy options for prostate cancer (PCa) typically are centered on docetaxel-based chemotherapy but are limited by the effects of multi-drug resistance. Recent advances have illustrated a role of contactin-1 (CNTN-1) in tumor chemoresistance, while the function and mechanism of CNTN-1 in the resistance of docetaxel in prostate cancer have not yet been elucidated.Material and methodsDocetaxel (Dox)-resistant PCa cell lines of PC3 (PC3-DR) and DU145 (DU145-DR) were established, and short hairpin RNA (shRNA) constructs targeting CNTN-1 were generated to analyze the effect of knockdown of CNTN-1 on PCa progression. Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing, transwell and western blotting analysis were used to analyze cell proliferation, apoptosis, migration, invasion and related protein expression levels, respectively.ResultsKnockdown of CNTN-1 in PC3-DR and DU145-DR cells attenuated cell proliferation, migration, invasion, EMT phenotype, and drug resistance, and increased cell apoptosis further reduced the tumorigenic phenotype. Knockdown of CNTN-1 resulted in an anti-tumor effect in the xenograft tumor model, and decreased activity of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway both in vitro and in vivo.ConclusionsThe results of the present study suggest that downregulation of CNTN-1 may be an important mechanism to reverse chemoresistance in Dox-resistant PCa progression, thus shedding light on the development of novel anti-tumor therapeutics for the treatment of PCa.

scholarly journals MST4 Kinase Inhibitor Hesperadin Attenuates Autophagy and Behavioral Disorder via the MST4/AKT Pathway in Intracerebral Hemorrhage Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiaodong Wu ◽  
Jinting Wu ◽  
Wenjie Hu ◽  
Qinghua Wang ◽  
Hairong Liu ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Kinase Inhibitor ◽  
Protein Localization ◽  
Akt Signaling ◽  
Behavioral Disorder ◽  
Akt Signaling Pathway ◽  
Akt Phosphorylation ◽  
Neurobehavioral Function

Background. The aim of this study was to explore the role of hesperadin in intracerebral hemorrhage (ICH) mice, with the involvement of the mammalian ste20-like kinase 4 (MST4)/AKT signaling pathway. Methods. All mice were divided into four groups: sham group, sham+hesperidin group, ICH group, and ICH+hesperadin group. The effects of hesperadin were assessed on the basis of brain edema and neurobehavioral function. Furthermore, we observed MST4, AKT, phosphorylation of AKT (pAKT), and microtubule-associated protein light chain 3 (LC3) by western blotting. Protein localization of MST4 and LC3 was determined by immunofluorescence. Results. The expression of MST4 was upregulated at 12 h and 24 h after ICH. Brain edema was significantly decreased and neurological function was improved in the hesperadin treatment group compared to the ICH group (P<0.05). Hesperadin decreases the expressions of MST and increases pAKT after ICH. Autophagy significantly increased in the ICH group, while hesperadin reduced this increase. Conclusion. Hesperadin provides neuroprotection against ICH by inhibiting the MST4/AKT signaling pathway.

scholarly journals Knockdown of lncRNA FOXD2-AS1 Inhibits Proliferation, Migration, and Drug Resistance of Breast Cancer Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qiaohong Nong ◽  
Shaokang Yu ◽  
Hui Hu ◽  
Xue Hu
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Invasion And Migration ◽  
And Migration ◽  
Mcf 7

Objective. In order to investigate the effect of lncRNA FOXD2-AS1 on breast cancer cells proliferation, migration, and drug resistance as well as its molecular mechanism. Methods. Real-time PCR was used to detect the expression of breast cancer tissues and cells from patients admitted to our hospital and the expression of lncRNA FOXD2-AS1 in MCF-7/ADR in adriamycin- (ADR-) resistant breast cancer cells. After interfering with or overexpressing lncRNA FOXD2-AS1 in MCF-7/ADR cells, cell proliferation, apoptosis, invasion, and migration were detected using CCK-8, flow cytometry, Transwell assay, and scratch test, respectively. The protein levels of PI3K, p-PI3K, AKT, and p-AKT in the PI3K/AKT signaling pathway were detected by Western blot. Results. lncRNA FOXD2-AS1 was upregulated in breast cancer tissues and cells and increased cell drug resistance to ADR. Downregulation of lncRNA FOXD2-AS1 inhibited invasion and migration of MCF-7/ADR cells, promoted apoptosis, increased chemosensitivity of MCF-7/ADR cells, and inhibited the activity of PI3K/AKT signaling pathway in MCF-7/ADR cells. Conclusions. lncRNA FOXD2-AS1 can promote the proliferation, invasion, migration, and drug resistance of breast cancer cells, inhibit apoptosis, and accelerate the development of breast cancer by positively regulating the PI3K/AKT signaling pathway.

scholarly journals The circadian rhythm and core gene Period2 regulate the chemotherapy effect and multidrug resistance of ovarian cancer through the PI3K signaling pathway

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Zhaoxia Wang ◽  
Honghong Wang ◽  
Hongrui Guo ◽  
Fengyan Li ◽  
Weiwei Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Circadian Rhythm ◽  
Signaling Pathway ◽  
Night Shift ◽  
Cpg Islands ◽  
Biological Clock ◽  
Death Receptor ◽  
Akt Signaling ◽  
Akt Signaling Pathway

Abstract Background: Ovarian cancer is the most lethal cancer in the female reproductive system. It has been shown that ‘time chemotherapy’ of ovarian cancer has an important impact on the chemotherapy effect and prognosis of patients, but the specific mechanism is not known. Methods: We designed a case–control study in strict accordance with epidemiological principles. We collected resection samples of ovarian cancer patients who worked night-shifts and those who did not, and analyzed the differences in protein expression. Through construction of a normal/circadian-rhythm disorder model of ovarian cancer in nude mice, we explored the molecular mechanism of a ‘biological clock’ rhythm on treatment of ovarian cancer. Results: Expression of interleukin (IL)-6, programmed cell death receptor-1 (PD-1) and programmed death ligand 1 (PD-L1) increased, and expression of tumor necrosis factor (TNF)-α, Period 1 (Per1) and Period 2 (Per2) decreased in the night-shift group. Methylation of CpG islands in the promoter of Per2 could result in its decreased expression in SKOV3/DDP (Cisplatin) cells. Dysrhythmia of the circadian clock: (i) had a negative effect on the chemotherapy effect against ovarian cancer; (ii) affected expression of immune factors and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Conclusion: The Per2 gene can affect the drug resistance of ovarian cancer by inhibiting the PI3K/Akt signaling pathway and then acting on its downstream drug-resistance factors, thereby providing a new target for ovarian cancer treatment.

scholarly journals Extracellular Matrix Proteins Confer Cell Adhesion-Mediated Drug Resistance Through Integrin αv in Glioblastoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Qi Yu ◽  
Weikun Xiao ◽  
Songping Sun ◽  
Alireza Sohrabi ◽  
Jesse Liang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Luciferase Reporter ◽  
Akt Signaling Pathway ◽  
Ecm Proteins ◽  
Cells Cultured

Chemotherapy resistance to glioblastoma (GBM) remains an obstacle that is difficult to overcome, leading to poor prognosis of GBM patients. Many previous studies have focused on resistance mechanisms intrinsic to cancer cells; the microenvironment surrounding tumor cells has been found more recently to have significant impacts on the response to chemotherapeutic agents. Extracellular matrix (ECM) proteins may confer cell adhesion-mediated drug resistance (CAMDR). Here, expression of the ECM proteins laminin, vitronectin, and fibronectin was assessed in clinical GBM tumors using immunohistochemistry. Then, patient-derived GBM cells grown in monolayers on precoated laminin, vitronectin, or fibronectin substrates were treated with cilengitide, an integrin inhibitor, and/or carmustine, an alkylating chemotherapy. Cell adhesion and viability were quantified. Transcription factor (TF) activities were assessed over time using a bioluminescent assay in which GBM cells were transduced with lentiviruses containing consensus binding sites for specific TFs linked to expression a firefly luciferase reporter. Apoptosis, mediated by p53, was analyzed by Western blotting and immunocytofluorescence. Integrin αv activation of the FAK/paxillin/AKT signaling pathway and effects on expression of the proliferative marker Ki67 were investigated. To assess effects of integrin αv activation of AKT and ERK pathways, which are typically deregulated in GBM, and expression of epidermal growth factor receptor (EGFR), which is amplified and/or mutated in many GBM tumors, shRNA knockdown was used. Laminin, vitronectin, and fibronectin were abundant in clinical GBM tumors and promoted CAMDR in GBM cells cultured on precoated substrates. Cilengitide treatment induced cell detachment, which was most pronounced for cells cultured on vitronectin. Cilengitide treatment increased cytotoxicity of carmustine, reversing CAMDR. ECM adhesion increased activity of NFκB and decreased that of p53, leading to suppression of p53-mediated apoptosis and upregulation of multidrug resistance gene 1 (MDR1; also known as ABCB1 or P-glycoprotein). Expression of Ki67 was correlative with activation of the integrin αv-mediated FAK/paxillin/AKT signaling pathway. EGFR expression increased with integrin αv knockdown GBM cells and may represent a compensatory survival mechanism. These results indicate that ECM proteins confer CAMDR through integrin αv in GBM cells.

scholarly journals Sphingosine-1-phosphate induces the migration and angiogenesis of EPCs through the Akt signaling pathway via sphingosine-1-phosphate receptor 3/platelet-derived growth factor receptor-β

2015 ◽  
Vol 20 (4) ◽  
Author(s):  
Hang Wang ◽  
Ke-Yin Cai ◽  
Wei Li ◽  
Hao Huang
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Akt Signaling ◽  
Platelet Derived Growth Factor ◽  
Akt Signaling Pathway ◽  
Akt Inhibitor ◽  
Sphingosine 1 Phosphate

AbstractEndothelial progenitor cells (EPCs) play a fundamental role in neoangiogenesis and tumor angiogenesis. Through the sphingosine-1-phosphate receptor 3 (S1PR3), sphingosine-1-phosphate (S1P) can stimulate the functional capacity of EPCs. Platelet-derived growth factor receptor-beta (PDGFR-β) contributes to the migration and angiogenesis of EPCs. This study aimed to investigate whether S1P induces the migration and angiogenesis of EPCs through the S1PR3/PDGFR-β/Akt signaling pathway. We used the Transwell system and the Chemicon In Vitro Angiogenesis Assay Kit with CAY10444 (an S1PR3 antagonist), AG1295 (a PDGFR kinase inhibitor) and sc-221226 (an Akt inhibitor) to examine the role of the S1PR3/PDGFR-β/Akt pathway in the S1Pinduced migration and angiogenesis of EPCs.

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