scholarly journals A Reversible Shift of Driver Dependence from EGFR to Notch1 in Non-Small Cell Lung Cancer as a Cause of Resistance to Tyrosine Kinase Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2022
Author(s):  
Francesca Iommelli ◽  
Viviana De Rosa ◽  
Cristina Terlizzi ◽  
Rosa Fonti ◽  
Rosa Camerlingo ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Parental Cell ◽  
Egfr Inhibitors ◽  
Simultaneous Increase ◽  
Adherent Cells ◽  
Binding Assays ◽  
Mesenchymal Transition ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Notch1 plays a key role in epithelial-mesenchymal transition (EMT) and in the maintenance of cancer stem cells. In the present study we tested whether high levels of activated Notch1 in oncogene-driven NSCLC can induce a reversible shift of driver dependence from EGFR to Notch1, and thus causing resistance to EGFR inhibitors. Adherent cells (parental) and tumor spheres (TS) from NSCLC H1975 cells and patient-derived CD133-positive cells were tested for EGFR and Notch1 signaling cascade. The Notch1-dependent modulation of EGFR, NCID, Hes1, p53, and Sp1 were then analyzed in parental cells by binding assays with a Notch1 agonist, DLL4. TS were more resistant than parental cells to EGFR inhibitors. A strong upregulation of Notch1 and a concomitant downregulation of EGFR were observed in TS compared to parental cells. Parental cell exposure to DLL4 showed a dose-dependent decrease of EGFR and a simultaneous increase of NCID, Hes1, p53, and Sp1, along with the dislocation of Sp1 from the EGFR promoter. Furthermore, an enhanced interaction between p53 and Sp1 was observed in TS. In NSCLC cells, high levels of active Notch1 can promote a reversible shift of driver dependence from EGFR to Notch1, leading to resistance to EGFR inhibitors.

scholarly journals Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jillian Hattaway Luttman ◽  
Ashley Colemon ◽  
Benjamin Mayro ◽  
Ann Marie Pendergast
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Abl Kinases ◽  
Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

Carvacrol Ameliorates Transforming Growth Factor-β1-Induced Extracellular Matrix Deposition and Reduces Epithelial-Mesenchymal Transition by Regulating The Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway In Hk-2 Cells

2021 ◽  
Vol 19 (4) ◽  
pp. 501-507
Author(s):  
Yunhe Gu ◽  
Peiyao Guo ◽  
Guangbiao Xu
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition ◽  
Dose Dependent

Transforming growth factor-β1 promotes excessive extracellular matrix deposition and epithelial-mesenchymal transition of tubular epithelial cells, thus stimulating the progression of renal fibrosis. Carvacrol has been shown to alleviate cardiac and liver fibrosis and attenuate renal injury. However, the role of carvacrol on renal fibrosis has not been examined. First, measurements using Cell Counting Kit-8 showed that carvacrol reduced cell viability of tubular epithelial cell line HK-2 in a dose-dependent fashion. Second, transforming growth factor-β1 induced excessive extracellular matrix deposition in HK-2 cells with enhanced collagen I, collagen IV, and fibronectin expression. However, carvacrol decreased the expression of collagen I, collagen IV in a dose-dependent manner and fibronectin to attenuate the extracellular matrix deposition in HK-2. Third, carvacrol attenuated TGF-β1-induced decrease of E-cadherin and increase of snail, vimentin, and alpha-smooth muscle actin in HK-2 cells. Transforming growth factor-β1-induced increase in PI3K and AKT phosphorylation in HK-2 were also reversed by carvacrol. Collectively, carvacrol ameliorates renal fibrosis through inhibition of transforming growth factor-β1-induced extracellular matrix deposition and epithelial-mesenchymal transition of HK-2 cells, providing potential therapy for the treatment of renal fibrosis.

scholarly journals Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6003
Author(s):  
Majd S. Hijjawi ◽  
Reem Fawaz Abutayeh ◽  
Mutasem O. Taha
Keyword(s):  
Anticancer Agents ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Resonance Energy ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Characteristic Analysis ◽  
Mesenchymal Transition ◽  
Intermolecular Contacts

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.

scholarly journals Berberine and Tinospora cordifolia exert a potential anticancer effect on colon cancer cells by acting on specific pathways

2019 ◽  
Vol 33 ◽  
pp. 205873841985556 ◽  
Author(s):  
Annalisa Palmieri ◽  
Luca Scapoli ◽  
Anastasia Iapichino ◽  
Laura Mercolini ◽  
Manuela Mandrone ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Tinospora Cordifolia ◽  
Active Principle ◽  
Mesenchymal Transition ◽  
Multiple Cell ◽  
Polymerase Chain ◽  
Dose Dependent ◽  
Cell Signaling Pathways

Berberine (BBR) is a natural active principle with potential antitumor activity. The compound targets multiple cell signaling pathways, including proliferation, differentiation, and epithelial–mesenchymal transition. The aim of this study was to elucidate the mechanisms behind the anticancer activity of BBR by comparing the effects of purified BBR with those of the extract of Tinospora cordifolia, a medicinal plant that produces this metabolite. The expression levels of a panel of 44 selected genes in human colon adenocarcinoma (HCA-7) cell line were quantified by real-time polymerase chain reaction (PCR). BBR treatment resulted in a time- and dose-dependent down regulation of 33 genes differently involved in cell cycle, differentiation, and epithelial–mesenchymal transition. The trend was confirmed across the two types of treatment, the two time points, and the different absolute dosage of BBR. These findings suggest that the presence of BBR in T. cordifolia extract significantly contributes to its antiproliferative activity.

Bortezomib-Induced Down-Regulation of KIT Is Mediated by Inhibition of Sp1 and NF-kB in AML1/ETO-Positive Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4211-4211
Author(s):  
Shujun Liu ◽  
Jiuxia Pang ◽  
Jianhua Yu ◽  
Zhongfa Liu ◽  
Lenguyen Huynh ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Kinase Inhibitors ◽  
Leukemic Cells ◽  
Therapeutic Approaches ◽  
Down Regulation ◽  
Activating Mutations ◽  
Binding Factor ◽  
Promote Cell Survival ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Abstract Activating mutations of KIT, encoding a type III receptor tyrosine kinase, are frequently detected in core binding factor AML (i.e., AML1/ETO and CBFB/MYH11 AML), promote cell survival and proliferation of leukemic cells and predict poor outcome. Kinase inhibitors (e.g., imatinib or PKC-412) have been shown to block constitutively activated KIT. However, novel therapeutic approaches that target mutated KIT are necessary, since resistance to these agents can be predicted in a substantial proportion of patients in these subgroups of AML. We observed that expression levels of KIT in AML1/ETO-positive Kasumi-1 cells are more than 25 fold higher than in AML1/ETO-negative AML cell lines (i.e., THP-1, K562, and MV4–11). We also found that in Kasumi-1 cells, bortezomib (Velcade), a proteasome inhibitor already used in the clinic, induces time- (60nM for 0, 1, 3, 6 12 and 24hr) and dose- (0, 1, 6, 20, 60 and 100nM for 24hr) dependent down-regulation (>90%) of total KIT expression. Noticeably, dephosphorylation of KIT occurred 6hr before reduction of the total KIT level after bortezomib exposure. We also found >50% down-regulation of KIT expression in patients’ primary blasts treated with 60nM bortezomib for 24hr and in Kasumi-1 cells treated with the proteasome inhibitor MG132 (300nM for 24hr). Down-regulation of KIT appeared to be associated with inhibition of NF-kB and Sp1, which is necessary for regulation of the KIT promoter activity by the SCL complex. In fact, treatment with bortezomib inactivated NF-kB and decreased transcription of Sp1 in Kasumi-1 cells. Furthermore, exposure to the NF-kB or Sp1 inhibitors parthenolide (30μM for 24hr) and mithramycin (100ng/ml for 24hr), respectively, resulted in a dose-dependent decrease in KIT expression in Kasumi-1 cells. When cells were treated with bortezomib (20nM) in combination with mithramycin (30ng/ml for 24hr), we observed synergy in down-regulation of KIT RNA and KIT protein. This correlated with growth arrest and increased cell death. Interestingly, the magnitude of these effects was higher when Kasumi-1 cells were pretreated with mithramycin for 24hr before being exposed to bortezomib. Taken all together, our data suggest that bortezomib downregulates KIT expression and might also inhibit KIT phosphorylation and should be considered in future therapeutic strategies targeting AML subgroups harboring mutated KIT.

scholarly journals Effects of acute ethanol administration on rat liver 5-aminolaevulinate synthase activity

1989 ◽  
Vol 262 (2) ◽  
pp. 491-496 ◽  
Author(s):  
A A B Badawy ◽  
C J Morgan ◽  
N R Davis
Keyword(s):  
Alcohol Dehydrogenase ◽  
Rat Liver ◽  
Intraperitoneal Administration ◽  
Reciprocal Relationship ◽  
Ethanol Administration ◽  
Simultaneous Increase ◽  
Acute Ethanol ◽  
Tryptophan Pyrrolase ◽  
Dose Dependent Decrease ◽  
Dose Dependent

1. Liver 5-aminolaevulinate (ALA) synthase activity of 24 h-starved rats is maximally increased at 4 h after intraperitoneal administration of a 1.6 g/kg body wt. dose of ethanol. Larger doses cause a dose-dependent decrease in the extent of this stimulation, exhibiting a reciprocal relationship with an elevation of hepatic haem concentration, as suggested by the simultaneous increase in the haem saturation of tryptophan pyrrolase. 2. ALA synthase induction by ethanol is abolished if the above increase in pyrrolase saturation with haem is enhanced by theophylline, but is potentiated when the increase in the haem saturation is inhibited by anti-lipolytic agents. 3. ALA synthase induction by ethanol is also inhibited by inhibitors of alcohol dehydrogenase and aldehyde dehydrogenase. Acetaldehyde and acetate are, however, not responsible; they both decrease ALA synthase activity and increase the haem saturation of tryptophan pyrrolase. These latter effects of acetaldehyde are not mediated by acetate. 4. ALA synthase activity is also stimulated by succinate, which, however, also increases the haem saturation of tryptophan pyrrolase. 5. Ethanol does not influence the rate of ALA synthase degradation. 6. It is suggested that ethanol increases rat liver ALA synthase activity as a result of its own metabolism by the alcohol dehydrogenase-dependent pathway by a mechanism not involving decreased degradation of the former enzyme or the participation of the metabolites acetaldehyde and acetate.

scholarly journals c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Weili Min ◽  
Chenyang He ◽  
Shuqun Zhang ◽  
Yang Zhao
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Sh2 Domain ◽  
Caspase 8 ◽  
Mesenchymal Transition ◽  
Epidermal Growth ◽  
Src Activation ◽  
Egfr Mutant

c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with “PDEP” motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs.

scholarly journals Anthocyanins fromVitis coignetiaePulliat Inhibit Cancer Invasion and Epithelial-Mesenchymal Transition, but These Effects Can Be Attenuated by Tumor Necrosis Factor in Human Uterine Cervical Cancer HeLa Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Jing Nan Lu ◽  
Won Sup Lee ◽  
Jeong Won Yun ◽  
Min Jeong Kim ◽  
Hye Jung Kim ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Hela Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Uterine Cervical Cancer ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Anticancer Effects ◽  
Dose Dependent ◽  
Necrosis Factor

Recently we have demonstrated that anthocyanins from fruits ofVitis coignetiaePulliat (AIMs) have anticancer effects. Here, we investigate the effects of AIMs on cell proliferation and invasion as well as epithelial-mesenchymal transition (EMT) which have been linked to cancer metastasis in human uterine cervical cancer HeLa cells. AIMs inhibited the invasion of HeLa cells in a dose-dependent manner. AIMs inhibited MMP-9 expression in a dose-dependent manner. AIMs inhibited the motility of HeLa cells in a wound healing test. AIMs still suppressed NF-κB activation induced by TNF. AIMs also inhibited EMT in HeLa cells. AIMs suppressed vimentin, N-cadherin, andβ-catenin expression and induced E-cadherin. AIMs also suppressed expression ofβ-catenin and Snail, which was regulated by GSK-3. These effects of AIMs were also limited in the HeLa cells treated with TNF. In conclusion, this study indicates that AIMs have anticancer effects by suppressing NF-κB-regulated genes and EMT, which relates to suppression of IκBαphosphorylation and GSK-3 activity, respectively. However, the effects of AIMs were attenuated in the TNF-high condition.

Effect of arsenic trioxide on epithelial-mesenchymal transition via induction of SH2?containing protein tyrosine phosphatase 1.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 76-76
Author(s):  
Jong-Jae Park ◽  
Moon Kyung Joo ◽  
Hyo Soon Yoo ◽  
Beom Jae Lee ◽  
Taehyun Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Protein Tyrosine Phosphatase ◽  
Epithelial Mesenchymal Transition ◽  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition ◽  
Protein Tyrosine ◽  
Dose Dependent

76 Background: Arsenic trioxide (ATO) is known to inhibit epithelial-mesenchymal transition (EMT) in hepatolocellular carcinoma and breast cancer cells, however, little has been reported in gastric cancer cells. In this study, we aimed to investigate the mechanism of ATO to inhibit signal transducer and activator of transcription 3 (STAT3) activity and EMT in gastric cancer cells. Methods: We performed wound closure assay and Matrigel invasion assay for functional studies of EMT, and western blot for measurement of protein markers using AGS gastric cancer cells. Results: Compared with control, 5 and 10 μM of ATO significantly inhibited cellular migration and inhibition in a dose-dependent manner. Furthermore, ATO significantly downregulated snail expression, a mesenchymal marker, and upregulated E-cadherin expression, an epithelial marker. We could observe that ATO induced SH2-containing protein tyrosine phosphatase 1 (SHP1), a non-receptor type protein tyrosine phosphatase, and subsequently downregulated phospho-STAT3 in a dose-dependent manner. To validate the molecular link between ATO and SHP1 to inhibit EMT in gastric cancer cell, we pre-treated 50 μM of pervanadate, a phosphatase inhibitor, before treatment of 10 μM ATO, and this significantly abolished anti-invasive effect by ATO in AGS cells. In xenograft tumor model, intraperitoneal injection of ATO significantly reduced the tumor volume and upregulated SHP-1 expression by immunohistochemistry stain compared with vehicle, which were reversed by ATO with pervanadate injection. Conclusions: Our findings suggest that ATO may show anti-EMT effects via induction of SHP1 and inhibition of STAT3 activity in gastric cancer cells.

Sign in / Sign up

Export Citation Format

Share Document