Showing papers on "Growth factor receptor inhibitor published in 2017"
TL;DR: It is shown that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8.
Abstract: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.
87 citations
01 May 2017
TL;DR: Monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials, and these drugs are not being further developed likely due to their metabolic toxicities.
Abstract: The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3′-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions.
85 citations
TL;DR: Bvacizumab is a monoclonal antibody that obstructs the binding of circulating vascular endothelial growth factor to its receptors and has been approved for the treatment of primary and recurrent ovarian cancer but also for many other solid tumors.
Abstract: The creation of new blood vessels from existing ones, which is a mechanism called “angiogenesis”, is essential in cancer to supply cancerous growth. Moreover, the development and the progression of the tumor and its metastases are the result of an efficient vascular response. Cancer cells release and activate different angiogenic growth factors and their receptors in the tumor microenvironment to promote the angiogenic process. The most important pro-angiogenic factor is the “Vascular Endothelial Growth Factor” (VEGF) because of its mitogen activity on vascular endothelium. Bevacizumab is a monoclonal antibody that obstructs the binding of circulating vascular endothelial growth factor to its receptors and has been approved for the treatment of primary and recurrent ovarian cancer but also for many other solid tumors.
68 citations
TL;DR: This work shows that miR-127, an embryo-expressing lung miRNA, was prominently induced in lung adenocarcinoma and correlated with poor prognosis, and identifies a novel molecular mechanism linking stemness, malignancy and inflammation, opening a new avenue for cancer treatment.
Abstract: The coordination between cellular differentiation and the mesenchymal/stem transition is essential for both embryo development and neoplasia, suggesting a mechanistic link between these two major processes. In this work we show that miR-127, an embryo-expressing lung miRNA, was prominently induced in lung adenocarcinoma and correlated with poor prognosis. Elevated miR-127 level drove a pronounced shift from the epithelial to the mesenchymal phenotype in cancer cells, and this shift was associated with their acquisition of stem-like traits, increased resistance to the epidermal growth factor receptor inhibitor and tumor-propagating potential. In contrast, antagonizing miR-127 markedly reversed this malignant transition, compromised the stem-like properties and the in vivo tumorigenic capability of cancer cells. Importantly, a regulatory loop involving the inflammatory signals NF-κB, miR-127 and tumor necrosis factor alpha-induced protein 3 was uncovered as a self-reinforcing circuitry that ensured an aggressive transition in lung cancer. Thus, this work identifies a novel molecular mechanism linking stemness, malignancy and inflammation, opening a new avenue for cancer treatment.
61 citations
TL;DR: The biology of ErbB receptors is reviewed, including their architecture, signaling, regulation and therapeutic strategies and the mechanisms of resistances offered by the receptors against small-molecule tyrosine kinases and resistance overcome implications of mAbs.
Abstract: The epidermal growth factor receptor (EGFR) is a transmembrane receptor with tyrosine kinase activity involved in regulation of cellular multiplication, survival, differentiation and metastasis. Our knowledge about function and complex management of these receptors has driving the development of specific and targeted treatment modalities for human cancers in the last 20 years. EGFR is the first receptor target against which monoclonal antibodies (mAb) have been evolved for cancer treatment. Here we review the biology of ErbB receptors, including their architecture, signaling, regulation and therapeutic strategies and the mechanisms of resistances offered by the receptors against small-molecule tyrosine kinases and resistance overcome implications of mAbs. The efficacy of EGFR-specific mAb in cancer depends on site specific extracellular region of EGFR, which has crucial role in process of dimerization and activation. This review highlights evolution of various resistance mechanisms due to consequences of current small-molecule anti-EGFR therapies.
50 citations
TL;DR: The results of the present study suggest that EGFR is a therapeutic target in breast CSCs and that abrogation of EGFR signalling along with chemotherapeutic drugs is an effective approach against breast cancer.
Abstract: The recurrence of breast cancer in patients is a persistent challenge to the medical fraternity. Breast tumor contains a small population of cells with high tumor initiating and metastatic potential, known as cancer stem cells (CSCs), which are resistant to existing chemotherapeutics. CSCs contribute to the aggressiveness of triple negative breast cancers (TNBCs), thereby necessitating the identification of molecular targets on breast CSCs. TNBC cell line MDA-MB-231, in comparison with MCF-7, demonstrated a higher expression of epidermal growth factor receptor (EGFR). Thus, the naturally occurring flavanone, chrysin, with limited potential as a chemotherapeutic agent, was structurally modified by designing an analog with EGFR binding affinity using a molecular docking approach and subsequently synthesised. Chrysin analog CHM-09 and known EGFR inhibitors demonstrated a comparable anti-proliferative, anti-migratory activity along with the induction of apoptosis and cell cycle arrest in MDA-MB-231. Furthermore, sorted CD24- /CD44+ -breast CSCs and CD24+ -breast cancer cells from MDA-MB-231 demonstrated a markedly high expression of EGFR in the former than in the latter. CHM-09 and EGFR inhibitors could perturb EGF-induced EGFR signalling of breast CSC proliferation, migration, mammosphere formation and mesenchymal tri-lineage differentiation. CHM-09 or EGFR inhibitors not only led to inactivation of EGFR downstream signalling pathways such as Akt, extracellular signal regulated kinase and signal transducer and activator of transcription 3, but also induction of mesenchymal-epithelial transition as confirmed by decreased N-cadherin and increased E-cadherin expression. Finally, combinatorial treatment of EGFR inhibitors and doxorubicin led to significant increase in breast CSCs responsiveness to a chemotherapeutic drug. The results of the present study suggest that EGFR is a therapeutic target in breast CSCs and that abrogation of EGFR signalling along with chemotherapeutic drugs is an effective approach against breast cancer.
43 citations
TL;DR: Possible interactions between FGFR2 signaling and several major pathways through which the aberrantly activated FG FR2 signaling may result in breast cancer development are discussed.
Abstract: Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates signaling for FGFs. Recent studies detected various point mutations of FGFR2 in multiple types of cancers, including breast cancer, lung cancer, gastric cancer, uterine cancer and ovarian cancer, yet the casual relationship between these mutations and tumorigenesis is unclear. Here we will discuss possible interactions between FGFR2 signaling and several major pathways through which the aberrantly activated FGFR2 signaling may result in breast cancer development. We will also discuss some recent developments in the discovery and application of therapies and strategies for breast cancers by inhibiting FGFR2 activities.
39 citations
TL;DR: The iron-regulated metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells, and the ErbB family of receptors are key inducers of carcinogenesis.
39 citations
TL;DR: It was found that clathrin-mediated endocytosis of epidermal growth factor receptor (EGFR) but not that of transferrin receptor requires EGFR-activated phospholipase Cγ1, Ca2+ signals, and protein kinase C.
Abstract: Clathrin-mediated endocytosis is a major regulator of cell-surface protein internalization. Clathrin and other proteins assemble into small invaginating structures at the plasma membrane termed clathrin-coated pits (CCPs) that mediate vesicle formation. In addition, epidermal growth factor receptor (EGFR) signaling is regulated by its accumulation within CCPs. Given the diversity of proteins regulated by clathrin-mediated endocytosis, how this process may distinctly regulate specific receptors is a key question. We examined the selective regulation of clathrin-dependent EGFR signaling and endocytosis. We find that perturbations of phospholipase Cγ1 (PLCγ1), Ca2+, or protein kinase C (PKC) impair clathrin-mediated endocytosis of EGFR, the formation of CCPs harboring EGFR, and EGFR signaling. Each of these manipulations was without effect on the clathrin-mediated endocytosis of transferrin receptor (TfR). EGFR and TfR were recruited to largely distinct clathrin structures. In addition to control of initiation and assembly of CCPs, EGF stimulation also elicited a Ca2+- and PKC-dependent reduction in synaptojanin1 recruitment to clathrin structures, indicating broad control of CCP assembly by Ca2+ signals. Hence EGFR elicits PLCγ1-calcium signals to facilitate formation of a subset of CCPs, thus modulating its own signaling and endocytosis. This provides evidence for the versatility of CCPs to control diverse cellular processes.
38 citations
TL;DR: The expression of PD-L1 can be regulated by EGFR signaling activation in ESCC, which indicates an important role for EG FR-mediated immune escape and potential molecular pathways for EGFR-targeted therapy and immunotherapy.
Abstract: Purpose The purpose of this study was to investigate the potential effect of activation of epidermal growth factor receptor (EGFR) signaling pathway on the expression of programmed death-ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) cells with EGFR overexpression. Methods Flow cytometry and Western blot methods were used to assess PD-L1 expression on ESCC cells when EGFR signaling pathway was activated by epidermal growth factor (EGF) with or without EGFR-specific inhibitor AG-1478, and then EGFR signaling array was applied to analyze the potential signaling pathways involved. Results This study found that PD-L1 expression increased significantly in an EGFR-dependent manner by the activation of EGFR signaling and decreased sharply when EGFR signaling was blocked. The upregulated expression of PD-L1 was not associated with EGFR-STAT3 signaling pathway, but may be affected by EGFR-PI3K-AKT, EGFR-Ras-Raf-Erk, and EGR-PLC-γ signaling pathways. Conclusion The expression of PD-L1 can be regulated by EGFR signaling activation in ESCC, which indicates an important role for EGFR-mediated immune escape and potential molecular pathways for EGFR-targeted therapy and immunotherapy.
38 citations
TL;DR: The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated.
Abstract: The epidermal growth factor receptor (EGFR) is implicated in various malignancies. The past decade has seen the development and widespread use of EGFR inhibitors for the successful treatment of such cancers. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated.
TL;DR: Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibro Blast Growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.
Abstract: Fibroblast growth factor receptors are growth factor receptor tyrosine kinases, exerting their roles in embryogenesis, tissue homeostasis, and development of breast cancer. Recent genetic studies have identified some subtypes of fibroblast growth factor receptors as strong genetic loci associated with breast cancer. In this article, we review the recent epidemiological findings and experiment results of fibroblast growth factor receptors in breast cancer. First, we summarized the structure and physiological function of fibroblast growth factor receptors in humans. Then, we discussed the common genetic variations in fibroblast growth factor receptors that affect breast cancer risk. In addition, we also introduced the potential roles of each fibroblast growth factor receptors isoform in breast cancer. Finally, we explored the potential therapeutics targeting fibroblast growth factor receptors for breast cancer. Based on the biological mechanisms of fibroblast growth factor receptors leading to the pathogenesis in breast cancer, targeting fibroblast growth factor receptors may provide new opportunities for breast cancer therapeutic strategies.
TL;DR: Results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing fibroblast growth factor 19 and dramatically extended the survival of the mice.
Abstract: Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, and JHH-7. In the Hep3B2.1-7 cell line, ASP5878 inhibited the phosphorylation of fibroblast growth factor receptor 4 and its downstream signaling molecules as well as induced apoptosis. Oral administration of ASP5878 at 3 mg/kg induced sustained tumor regression in a subcutaneous xenograft mouse model using Hep3B2.1-7. In HuH-7, an orthotopic xenograft mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival of the mice. These results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing fibroblast growth factor 19. Mol Cancer Ther; 16(1); 68-75. ©2016 AACR.
TL;DR: It is suggested that CD200-positive CAFs can augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib and may possess far reaching applications in the therapeutic use of EGfr-TKIs.
Abstract: Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.
TL;DR: Evidence supporting the oncogenic potential of NFAT3 is provided and it is suggested that CDK3-mediated phosphorylation ofNFAT3 has an important role in skin tumorigenesis.
Abstract: The nuclear factor of activated T cells (NFAT) family proteins are transcription factors that regulate the expression of pro-inflammatory cytokines and other genes during the immune response. Although the NFAT proteins have been extensively investigated in the immune system, their role in cancer progression remains controversial. Here, we report that NFAT3 is highly expressed in various skin cancer cell lines and tumor tissues. Knockdown of endogenous NFAT3 expression by short hairpin RNA (shRNA) significantly inhibited tumor cell proliferation, colony formation and anchorage-independent cell growth. Furthermore, results of the mammalian two-hybrid assay showed that cyclin-dependent kinase 3 (CDK3) directly interacted with NFAT3 and phosphorylated NFAT3 at serine 259 (Ser259), which enhanced the transactivation and transcriptional activity of NFAT3. The phosphorylation site of NFAT3 was critical for epidermal growth factor (EGF)-stimulated cell transformation of the HaCaT immortalized skin cell line and mutation of NFAT3 at Ser259 led to a reduction of colony formation in soft agar. We also found that overexpressing wildtype NFAT3, but not mutant NFAT3-S259A, promoted A431 xenograft tumor growth. Importantly, we showed that CDK3, NFAT3 and phosphorylated NFAT3-Ser259 were highly expressed in skin cancer compared with normal skin tissues. These results provided evidence supporting the oncogenic potential of NFAT3 and suggested that CDK3-mediated phosphorylation of NFAT3 has an important role in skin tumorigenesis.
TL;DR: This study provides an important screening of potential polyphenolic compounds for drug development to overcome TKI resistance in advanced lung cancer.
Abstract: Background: Polyphenolic phytochemicals are natural compounds, easily found in fruits and vegetables. Importantly, polyphenols have been intensively studied as excellent antioxidant activity which contributes to anticancer function of the natural compounds. Lung cancer has been reported to mainly account for cancer-related deaths in the world. Moreover, epidermal growth factor receptor tyrosine kinase inhibitor (TKI) resistance is one of the biggest issues in cancer treatment, especially in nonsmall cell lung cancer (NSCLC). Even though several studies both in preclinical and clinical trials have showed promising therapeutic effects of polyphenolic compounds in anticancer therapy, the function of the natural compounds in TKI-resistant (TKIR) lung cancer remains poorly studied. Objective: The aim of this study is to screen polyphenolic compounds as potential anticancer adjuvants which suppress TKIR lung cancer. Materials and Methods: Colony formation and thiazolyl blue tetrazolium blue assay were performed in the pair-matched TKI-sensitive (TKIS) versus TKIR tumor cell lines to investigate the therapeutic effect of polyphenolic compounds in TKIR NSCLC. Results: Our data show that equol, kaempferol, resveratrol, and ellagic acid exhibit strong anticancer effect in HCC827 panel. Moreover, the inhibitory effect of most of tested polyphenolic compounds was highly selective for TKIR lung cancer cell line H1993 while sparing the TKIS one H2073. Conclusion: This study provides an important screening of potential polyphenolic compounds for drug development to overcome TKI resistance in advanced lung cancer. Abbreviations used: EGFR: Epidermal growth factor receptor, EMT: Epithelial-to-mesenchymal transition, GTP: Green tea polyphenols, IGF1R: Insulin-like growth factor 1 receptor, MET: Met proto-oncogene, MTT: Thiazolyl blue tetrazolium blue, NSCLC: Non-small cell lung cancer, ROS: Reactive oxygen species, RTK: Receptor tyrosine kinase, STAT3: Signal transducer and activator of transcription 3, TKIR: TKI-resistant, TKIs: Tyrosine kinase inhibitors, TKIS: TKI-sensitive.
TL;DR: Findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro, and further in vivo studies are warranted to explore the anti-tumour activity of tivzanib in combinatorial approaches in GBM.
Abstract: Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.
TL;DR: This work aims to deepen in the role played by extracellular S100A7 in the tumor microenvironment, offering a new integrative insight of its mechanism of action on each cellular compartment (tumor, endothelial, immune and fibroblast).
Abstract: Within the tumor, malignant and stromal cells support each other by secreting a wide variety of growth factors and cytokines, allowing tumor growth and disease progression. The identification and regulation of those key factors in this crosstalk has opened the opportunity to develop new therapeutic strategies that not only act on the tumor cells but also on the stroma. Among these factors, S100A7 protein has gained interest in the last years. With key roles in cell motility its expression correlates with increased tumor growth, angiogenesis and metastatic potential. This work aims to deepen in the role played by extracellular S100A7 in the tumor microenvironment, offering a new integrative insight of its mechanism of action on each cellular compartment (tumor, endothelial, immune and fibroblast). As a result, we demonstrate its implication in cell migration and invasion, and its important contribution to the formation of a proinflammatory and proangiogenic environment that favors tumor progression and metastasis. Furthermore, we define its possible role in the pre-metastatic niche formation. Considering the relevance of S100A7 in cancer progression, we have developed neutralizing monoclonal antibodies, reporting for the first time the proof of principle of this promising therapeutic strategy for cancer treatment.
TL;DR: This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway through the inhibition of the RAF-MEK-ERK signaling pathway.
Abstract: Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinas...
TL;DR: It is shown that dual-specificity tyrosine phosphorylation-kinase 2 (DYRK2) is a novel negative regulator for formation of breast cancer stem cells and that Krupple-like factor 4 (KLF4) serves as a key mediator of DyrK2’s control over the cancer stem phenotype.
Abstract: Whereas accumulating studies have supported the cancer stem cell theory, a specific therapy targeting a cancer stem cell subpopulation has not been established. Here, we show that dual-specificity tyrosine phosphorylation-kinase 2 (DYRK2) is a novel negative regulator for formation of breast cancer stem cells. Downregulation of DYRK2 promotes cancer stem-like traits in vitro, tumourigenesis in vivo and the proportion of the cancer stem cell population in human breast cancer tissues. We found that Krupple-like factor 4 (KLF4) serves as a key mediator of DYRK2's control over the cancer stem phenotype. Reduced DYRK2 expression increases KLF4 expression, which induces cancer stem-like properties. We identified androgen receptor (AR) as a transcription factor binding to the KLF4 promoter region; this process is dependent on DYRK2 kinase activity. Our findings delineate a mechanism of cancer stem cell regulation by the DYRK2-AR-KLF4 axis in breast cancer. Targeting of this pathway may be a promising strategy against breast cancer stem cells.
TL;DR: It is demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
Abstract: Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
TL;DR: It was observed that miR-296-5p potentiated the invasion of various GBM cells including LN229, T98G, and U87MG and suggested it as a promising therapeutic target for GBM.
Abstract: Glioblastomas (GBM) are very difficult to treat and their aggressiveness is one of the main reasons for this as well as for the frequent recurrences. MicroRNAs post-transcriptionally regulate their target genes through interaction between their seed sequence and 3'UTR of the target mRNAs. We previously reported that miR-296-3p is regulated by neurofibromatosis 2 (NF2) and enhances the invasiveness of GBM cells via SOCS2/STAT3. In this study, we investigated whether miR-296-5p, which originates from the same precursor miRNA as miR-296-3p, can increase the invasiveness of GBM cells. It was observed that miR-296-5p potentiated the invasion of various GBM cells including LN229, T98G, and U87MG. Through bioinformatics approaches, two genes were identified as miR-296-5p targets: caspase-8 (CASP8) and nerve growth factor receptor (NGFR). From results obtained from Ago2 immunoprecipitation and luciferase assays, we found that miR-296-5p downregulates CASP8 and NGFR through direct interaction between seed sequence of the miRNA and 3'UTR of the target mRNA. Knockdown of CASP8 or NGFR also increased the invasive ability of GBM cells, indicating that CASP8 and NGFR are involved in potentiation of invasiveness by miR-296-5p. Consistent with our findings, CASP8 was downregulated in brain metastatic lung cancer cells, which have a high level of miR-296-5p, compared to parental cells, suggesting that miR-296-5p may be generally associated with the acquisition of invasiveness. Collectively, our results implicate miR-296-5p as a potential cause of invasiveness in cancer and suggest it as a promising therapeutic target for GBM.
TL;DR: The results of the present study suggested that the deregulation of miRNA-193b may affect cell growth in colon cancer via the TGF-β and SMAD3 signaling pathways.
Abstract: MicroRNA-193b (miRNA-193b) is often differentially expressed and is an important regulator of gene expression in colon cancer. The aim of the present study was to determine whether miRNA-193b affects cell growth in colon cancer and to investigate the potential underlying mechanisms. Patients with colorectal cancer (CRC; n=20) and healthy volunteers (n=10) were enrolled from the Department of Gastrointestinal Surgery Center, First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China). Western blot analysis was used to evaluate the protein expression of SMAD3 and transforming growth factor-β (TGF-β) in the patient samples. It was determined that miRNA-193b expression was markedly elevated in the CRC tissue samples. Furthermore, silencing of miRNA-193bin SW620 CRC cells by specific inhibitors significantly reduced the cell proliferation and induced apoptosis. In addition, the downregulation of miRNA-193b significantly activated the protein expression of SMAD3 and TGF-β, and promoted caspase-3 activity in SW620 cells. The results of the present study suggested that the deregulation of miRNA-193b may affect cell growth in colon cancer via the TGF-β and SMAD3 signaling pathways.
TL;DR: The aim of the present study was to provide an overview of the key adverse events reported for EGFR-TKIs in clinical trials including patients with advanced NSCLC.
Abstract: Recent progress in the research on the molecular biology of lung cancer revealed that the clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is associated with the presence of activating EGFR mutations. Three EGFR-TKIs, namely afatinib, erlotinib and gefitinib, are currently available for the treatment of patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). Due to the dearth of published phase III trials prospectively evaluating the effects of one EGFR-TKI in comparison with another in such patients, the decision-making regarding which agent to recommend to any given patient lies with the treating physician. Given the potential long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these drugs in such patients may differ from those observed in unselected patients. The aim of the present study was to provide an overview of the key adverse events (rash, diarrhea, hepatotoxicity and interstitial lung disease) reported for EGFR-TKIs in clinical trials including patients with advanced NSCLC.
TL;DR: Current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development are summarized.
Abstract: Transforming growth factor-β (TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in various diseases including tumor formation. Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), also play key roles in the development and progression of many types of tumors. It has been realized that TGF-β signaling and RTK pathways interact with each other and their interplay is important for cancer development. They are mutually regulated and cooperatively modulate cell survival and migration, epithelial-mesenchymal transition, and tumor microenvironment to accelerate tumorigenesis and tumor metastasis. RTKs can modulate Smad-dependent transcription or cooperate with TGF-β to potentiate its oncogenic activity, while TGF-β signaling can in turn control RTK signaling by regulating their activities or expression. This review summarizes current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development.
TL;DR: Structure‐based design and synthesis of pyrimidine containing reversible epidermal growth factor receptor (EGFR) inhibitors 1a–d exhibited excellent anticancer activity at low micromolar level in lung, colon and breast cancer cell lines.
Abstract: Structure-based design and synthesis of pyrimidine containing reversible epidermal growth factor receptor (EGFR) inhibitors 1a-d are reported The compounds (1a-d) inhibited the EGFR kinase activity in vitro with IC50 range 740 nm to 3 μm mRNA expression of EGFR downstream target genes, that is twist, c-fos and aurora were found to be altered upon treatment with compounds 1a-d The compounds 1a-d exhibited excellent anticancer activity at low micromolar level (32-9 μm) in lung, colon and breast cancer cell lines Furthermore, compounds induced the alteration in mitochondrial membrane potential and reactive oxygen species level and Selected compound 1b was found to increase sub-G1 population indicative of cell death, the mode of cell death was apoptotic as evident from Annexin V verses propidium iodide assay Molecular modelling further helped to investigate the binding recognition pattern of the compounds in ATP binding EGFR domain similar to erlotinib and dissimilar to WZ4002
TL;DR: The results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor Necrosis factor receptors 1 to influence the growth of MCF-7 cell.
Abstract: Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to influence the growth of MCF-7 cell.
TL;DR: It was revealed that Que inhibited RB cell growth and invasion in vitro in a dose-dependent manner, with 100 µM Que exhibiting the strongest inhibitory effect.
Abstract: Retinoblastoma (RB) is the most common malignant intraocular cancer in teenagers, occurrence of which depends on the mutation of multiple genes. Among all the signaling pathways involved in the oncogenesis of RB, the process of angiogenesis has been demonstrated to be associated with the local invasive growth and metastasis of this cancer type. Quercetin (Que) is a typical flavonoid and has been reported to inhibit angiogenesis in various types of tumors. In the present study, the effect of Que on RB cells and angiogenesis of RB was evaluated. The human RB Y79 cell line was subjected to treatment with Que of various concentrations. Viability, invasion and migration ability and apoptosis of Y79 cells were subsequently measured to assess the effect of Que on RB cells. In addition, the expression of vascular endothelial growth factor receptor (VEGFR) was also quantified. It was revealed that Que inhibited RB cell growth and invasion in vitro in a dose-dependent manner, with 100 µM Que exhibiting the strongest inhibitory effect. In addition, Que downregulated the expression of VEGFR, which was an indicator of the blockade of angiogenesis in RB by targeting VEGF. The effect of Que on angiogenesis was also observed to be dose-dependent. The results of the present study indicated that Que may be a potential anti-RB therapy due to its anti-angiogenesis effect.
TL;DR: Wang et al. as mentioned in this paper found that the expression of miR-205 was low in cervical cancer cell lines and tissues, compared with matched non-tumor tissues and human endocervical epithelial cells.
Abstract: MicroRNAs are a kind of small and non-coding RNAs, which have been demonstrated to play an important role in the progression of human cervical cancer. Here, we found that the expression of miR-205 was low in cervical cancer cell lines and tissues, compared with matched non-tumor tissues and human endocervical epithelial cells. Also, miR-205 was inversely correlated with histological differentiation, metastasis, International Federation of Gynecology and Obstetrics stage, and the expression of insulin-like growth factor receptor 1 messenger RNA and protein. Besides, miR-205 or insulin-like growth factor receptor 1 expression is an independent prognostic factor. Mechanically, ectopic expression of miR-205 decreased proliferation, colony formation, and some proliferation/apoptosis-related proteins in cervical cancer cells. Ectopic expression of miR-205 caused G1 arrest. Luciferase reporter assays confirmed that binding of miR-205 to the 3′ untranslated region of insulin-like growth factor receptor 1 may pote...
TL;DR: The results of the present study suggest that H19 may function as a competing endogenous RNA to regulate HER2 expression by sequestering let‑7c in GC cells.
Abstract: Long non‑coding RNA (lncRNA) H19 has been suggested to serve important roles in the progression of gastric cancer (GC); however, the mechanism involved is largely unknown. The present study aimed to investigate the mechanism underlying the effect of H19 on human epidermal growth factor receptor (HER2) expression. Let‑7c belongs to the let‑7 family, which has been reported to be downregulated in cancers and considered to serve as a tumor suppressor. Let‑7c has been negatively associated with the expression of human epidermal growth factor receptor 2 (HER2). Reverse transcription‑quantitative polymerase chain reaction was used to examine the expression levels of H19 and let‑7c in GC tissues and cell lines. HER2 protein expression levels were examined using immunohistochemistry and western blot analyses. The effect of H19 on let‑7c and HER2 expression was analyzed following transfection of small interfering RNA targeting H19 in GC cells. The results indicated that the expression levels of H19 lncRNA in GC tissue samples were significantly higher when compared with that in matched benign adjacent tissue samples (P<0.001). H19‑silenced GC cells exhibited significantly increased let‑7c expression and decreased HER2 protein expression levels. Assessment of tumor diameter and pathological tumor stage suggested that increased H19 expression was associated with a poorer prognosis in patients with GC. The results of the present study suggest that H19 may function as a competing endogenous RNA to regulate HER2 expression by sequestering let‑7c in GC cells. The present study has aided the understanding of the mechanism of H19 lncRNA in GC, and has provided evidence for the application of lncRNA‑based diagnostic and therapeutic strategies for GC.