Figure - available from: Cancers
This content is subject to copyright.
Receptor Tyrosine Kinase (RTK) domains and activation process. This schematic representation depicts the dimerization process of RTKs following activation by their specific ligands. A series of self-phosphorylation and phosphorylation of proteins linked to the intracellular protein binding domain of RTKs initiates downstream signaling cascades.
Source publication
The Hippo pathway plays a critical role in tissue and organ growth under normal physiological conditions, and its dysregulation in malignant growth has made it an attractive target for therapeutic intervention in the fight against cancer. To date, its complex signaling mechanisms have made it difficult to identify strong therapeutic candidates. Hip...
Similar publications
In the last decade, LMTK3 (lemur tyrosine kinase 3) has emerged as an important player in breast cancer, contributing to the advancement of disease and the acquisition of resistance to therapy through a strikingly complex set of mechanisms. Although the knowledge of its physiological function is largely limited to receptor trafficking in neurons, t...
Lung cancer, of which non-small lung cancer is the most common subtype, represents the leading cause of cancer related-death worldwide. It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis. In recent years, more of these so-called oncogenic drivers have been identified, and...
Citations
... Notably, since YAP lacks a DNA-binding domain, other transcription factors need to be involved to function properly, and among these transcription factors, the TEAD family is the most closely related [65][66][67]. In malignancies, many signalling pathways intersect with the Hippo pathway, of which the RTK/ERK signalling pathway is a prominent pathway [38,39,68]. Given that EphA2 belongs to the RTK family, EphA2 may play a similar role. ...
Ephrin receptor A2 (EphA2), a member of the Ephrin receptor family, is closely related to the progression of oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs) play essential roles in OSCC development and occurrence. The underlying mechanisms between EphA2 and CSCs, however, are not yet fully understood. Here, we found that EphA2 was overexpressed in OSCC tissues and was associated with poor prognosis. Knockdown of EphA2 dampened the CSC phenotype and the tumour-initiating frequency of OSCC cells. Crucially, the effects of EphA2 on the CSC phenotype relied on KLF4, a key transcription factor for CSCs. Mechanistically, EphA2 activated the ERK signalling pathway, promoting the nuclear translocation of YAP. Subsequently, YAP was bound to TEAD3, leading to the transcription of KLF4. Overall, our findings revealed that EphA2 can enhance the stemness of OSCC cells, and this study identified the EphA2/KLF4 axis as a potential target for treating OSCC.
... They are not only receptors for growth factors but also enzymes that can catalyze phosphorylation of downstream target proteins. RTKs are also upstream targets of the PI3K/AKT signaling pathway and can regulate AKT expression, thus affecting cancer cell proliferation and apoptosis [36,37]. Abnormal activation of receptor proteins in the RTKs family (such as EGFR and PDGFR) is associated with various tumors and is also an important target for tumor drug research. ...
Objective: To investigate the inhibitory effect of EVO on colorectal cancer (CRC) growth and further explore the potential mechanism involving the RTKs-mediated PI3K/AKT/p53 signaling pathway.
Methods: Firstly, the inhibitory effect of EVO on CRC cells was detected in vitro by cell viability assay and colony formation assay. The effects of EVO on spatial migration and invasion capacity of cells were detected by Transwell assay. The effects of EVO on apoptosis and cycle of cells were detected by flow cytometry. Then, the molecular mechanism of EVO against CRC was revealed by qRT-PCR and Western blot. Finally, the excellent anti-tumour activity of EVO was verified by in vivo experiments.
Results: The results demonstrated that EVO exerts inhibitory effects on CRC cell proliferation, invasion, and colony formation. The cell cycle assay revealed that EVO induces G1/S phase arrest. Through RNA seq, we explored the influence of EVO on the transcriptional profile of colon cancer and observed significant activation of RTKs and the PI3K/AKT pathway, along with its downstream signaling pathways. Furthermore, we observed upregulation of p53 proteins by EVO, which led to the inhibition of Bcl-2 expression and an increase in Bax expression. Consistently, EVO exhibited remarkable suppression of tumor xenograft growth in nude mice.
Conclusion: This study confirmed that EVO inhibits the proliferation of CRC cells and promotes cell apoptosis. The possible mechanism of action is inhibiting the expression of the RTK protein family, activating the PI3K/AKT/p53 apoptotic signaling pathway, thereby inhibiting Bcl-2 expression and increasing Bax expression, promoting apoptosis of CRC cells. As a natural product, EVO has very high potential application value.
... This allows for non-invasive visualization of these targets in the body, aiding in the diagnosis, staging and monitoring of response to treatment in various cancers [6,7]. This newer imaging could reveal the expression of RTKs (Figure 1), which are one of most explored targets for developing anticancer therapeutic and imaging agents [7][8][9][10][11][12] (Table 1). ImmunoPET has, in fact, shown excellent specificity and sensitivity in detecting tumors expressing RTKs and assessing changes in expression levels in response to targeted kinase inhibition [9]. ...
Simple Summary
Receptor tyrosine kinases (RTKs) are a family of transmembrane proteins that play crucial roles in regulating various cellular processes. The introduction of ImmunoPET targeting RTKs by specific monoclonal antibodies (mAbs) or antibody fragments is regarded as a promising tool for imaging treatment efficacy and developing anticancer drugs. Herein, we review the current clinical research on ImmunoPET targeting RTKs, with particular interest in the epidermal growth factor family, or HER family, and vascular endothelial-derived growth factor/receptor.
Abstract
Receptor tyrosine kinases, or RTKs, are one large family of cell surface receptors involved in signal transduction, which represent an integral part of the signaling pathways. They play a crucial role in most important cellular processes, starting with the cell cycle, proliferation and differentiation, as well as cell migration, metabolism and survival. The introduction of ImmunoPET evaluating the expression of RTKs by specific monoclonal antibodies (mAbs) or antibody fragments is regarded as a promising tool for imaging treatment efficacy and developing anticancer therapeutics. Our review focuses mainly on the current clinical research regarding ImmunoPET targeting RTKs, with particular interest in the epidermal growth factor family, or HER family, and vascular endothelial-derived growth factor/receptor.
... Altogether, through this comprehensive characterization, we were able to underline the strong upregulation of major known canonical effectors of RAS. Nonetheless, signalling via the PI3K-mTOR and Hippo pathways was also observed (detailed in the figure legend), suggesting a considerable level of crosstalk [32,33]. Thus, despite being exclusively Ras-triggered, our model outlines the complexity of effects on oncogenic signalling via various effectors. ...
Background
Upregulation of the mitogen-activated protein kinase (MAPK) cascade is common in hepatocellular carcinoma (HCC). Neuroblastoma RAS viral oncogene homolog (NRAS) is mutated in a small percentage of HCC and is hitherto considered insufficient for hepatocarcinogenesis. We aimed to characterize the process of N-Ras-dependent carcinogenesis in the liver and to identify potential therapeutic vulnerabilities.
Methods
NRAS V12 plasmid was delivered into the mouse liver via hydrodynamic tail vein injection (HTVI). The resulting tumours, preneoplastic lesions, and normal tissue were characterized by NanoString® gene expression analysis, Western Blot, and Immunohistochemistry (IHC). The results were further confirmed by in vitro analyses of HCC cell lines.
Results
HTVI with NRAS V12 plasmid resulted in the gradual formation of preneoplastic and neoplastic lesions in the liver three months post-injection. These lesions mostly showed characteristics of HCC, with some exceptions of spindle cell/ cholangiocellular differentiation. Progressive upregulation of the RAS/RAF/MEK/ERK signalling was detectable in the lesions by Western Blot and IHC. NanoString® gene expression analysis of preneoplastic and tumorous tissue revealed a gradual overexpression of the cancer stem cell marker CD133 and Dual Specificity Phosphatases 4 and 6 (DUSP4/6). In vitro, transfection of HCC cell lines with NRAS V12 plasmid resulted in a coherent upregulation of DUSP4 and DUSP6. Paradoxically, this upregulation in PLC/PRF/5 cells was accompanied by a downregulation of phosphorylated extracellular-signal-regulated kinase (pERK), suggesting an overshooting compensation. Silencing of DUSP4 and DUSP6 increased proliferation in HCC cell lines.
Conclusions
Contrary to prior assumptions, the G12V NRAS mutant form is sufficient to elicit hepatocarcinogenesis in the mouse. Furthermore, the upregulation of the MAPK cascade was paralleled by the overexpression of DUSP4, DUSP6, and CD133 in vivo and in vitro. Therefore, DUSP4 and DUSP6 might fine-tune the excessive MAPK activation, a mechanism that can potentially be harnessed therapeutically.
... Receptor tyrosine kinases (RTKs) are a type of transmembrane protein that transduce stimulatory signals to downstream proteins in a ligand-dependent manner (28). Aberrant activation of the RTK pathway usually occurs in tumorigenesis and malignant progression (29). ...
Lung cancer is one of the most common malignant solid tumors and the leading cause of cancer-associated mortality worldwide. Endocytosis is an essential physiological activity for cells to maintain membrane homeostasis, and has been reported to serve an important role in tumorigenesis and progression. In the present study, the aim was to construct a prognostic prediction model of endocytosis-associated genes for patients with lung adenocarcinoma (LUAD). The endocytosis-associated gene signature was established using Lasso Cox regression analysis using the training set of the LUAD cohort from The Cancer Genome Atlas (TCGA) database, and verified using two datasets from the Gene Expression Omnibus (GEO) database. Kaplan-Meier survival curves were used to evaluate the effectiveness of the prognostic evaluation of patients with LUAD. Differentially expressed genes were screened in the tumor tissue of patients compared with paired paracancerous tissues. A series of candidate genes associated to the prognosis of patients with LUAD was obtained using univariate Cox's regression analysis. Using the Lasso Cox regression analysis, an appropriate risk model with 18 endocytosis-associated genes was established. A high-risk score was positively correlated with a higher tumor stage and pathologic grade. Patients with LUAD and high-risk scores had shorter survival times, increased intratumor heterogeneities and immune cell infiltration into tumor tissues, compared with those patients with LUAD and low-risk scores. The endocytosis inhibitor chloroquine could repress proliferation and increase the apoptosis of lung cancer cells. In summary, a novel endocytosis-associated gene signature was constructed using TCGA and GEO datasets. Patients with LUAD and high-risk scores, as calculated by the signature, had a poor prognosis and short survival time.
... We validated the downregulation of selected genes from the YAP1-signature in RNF40-silenced BLBC cells using the RNF40-specific siRNA smart pool as well as the single siRNAs ( Fig. 4C, Fig. S1G). The YAP1 activity is negatively regulated via phosphorylation at serine 127 (pYAP1-S127) by the Large Tumor Suppressor kinases 1 and 2 (LATS1/2) of the Hippo signaling cascade [33]. Therefore, we leveraged a specific LATS1/2 inhibitor (LATSi) and observed a rescue of YAP1-responsive genes expression in RNF40-silenced HCC1806 cells (Fig. 4D). ...
Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype to treat due to the lack of targeted therapies. Cancer stem cells (CSCs) are strongly enriched in TNBC lesions and are responsible for the rapid development of chemotherapy resistance and metastasis. Ubiquitin-based epigenetic circuits are heavily exploited by CSCs to regulate gene transcription and ultimately sustain their aggressive behavior. Therefore, therapeutic targeting of these ubiquitin-driven dependencies may reprogram the transcription of CSC and render them more sensitive to standard therapies. In this work, we identified the Ring Finger Protein 40 (RNF40) monoubiquitinating histone 2B at lysine 120 (H2Bub1) as an indispensable E3 ligase for sustaining the stem-cell-like features of the growing mammary gland. In addition, we found that the RNF40/H2Bub1-axis promotes the CSC properties and drug-tolerant state by supporting the glycolytic program and promoting pro-tumorigenic YAP1-signaling in TNBC. Collectively, this study unveils a novel tumor-supportive role of RNF40 and underpins its high therapeutic value to combat the malignant behavior of TNBC.
... The oncogenic activity of RTK signaling pathways is often amplified by the formation of a positive feedback loop with the Hippo pathway 74,75 . When the Hippo pathway is dysregulated, the transcription factor YAP1 accumulates in the nucleus 76,77 . ...
The Tasmanian devil (Sarcophilus harrisii) is endangered due to the spread of Devil Facial Tumour Disease (DFTD), a contagious cancer with no current treatment options. Here we test whether seven recently characterized Tasmanian devil cathelicidins are involved in cancer regulation. We measured DFTD cell viability in vitro following incubation with each of the seven peptides and describe the effect of each on gene expression in treated cells. Four cathelicidins (Saha-CATH3, 4, 5 and 6) were toxic to DFTD cells and caused general signs of cellular stress. The most toxic peptide (Saha-CATH5) also suppressed the ERBB and YAP1/TAZ signaling pathways, both of which have been identified as important drivers of cancer proliferation. Three cathelicidins induced inflammatory pathways in DFTD cells that may potentially recruit immune cells in vivo. This study suggests that devil cathelicidins have some anti-cancer and inflammatory functions and should be explored further to determine whether they have potential as treatment leads.
... The Hippo-YAP1 pathway is emerging as an effective bypass mechanism to mitogenactivated protein kinase (MAPK) pathway inhibition [12,13]. Hippo-YAP1 acts via the activation of transcriptional coactivator proteins, transcriptional coactivators yes-associated protein 1/transcriptional activator with PDZ-binding motif (YAP1 and TAZ), which interact with transcription factors from the TEAD-family (transcriptional enhanced associate domain 1-4; DNA binding transcription factors) and thereby regulate the transcription of genes required for cell survival and cell proliferation [14]. ...
KRASG12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRASG12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRASG12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRASG12C inhibitors in KRASG12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRASG12C-driven NSCLC cells, enhance KRASG12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRASG12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRASG12C and TEAD leads to a specific dual cell cycle arrest in KRASG12C NSCLC cells.
... Therefore, RTKs are of high pharmaceutical value and have been targets for numerous drugs designed for clinical scenarios regarding targeted therapies. Moreover, they have been the basis of research for new potential drugs [6,[17][18][19][20][21][22]. ...
Receptor tyrosine kinases (RTKs) form a highly important group of protein receptors of the eukaryotic cell membrane. They control many vital cellular functions and are involved in the regulation of complex signaling networks. Mutations in RTKs have been associated with different types of cancers and other diseases. Although they are very important for proper cell function, they have been experimentally studied in a limited range of eukaryotic species. Currently, there is no available database for RTKs providing information about their function, expression, and interactions. Therefore, the identification of RTKs in multiple organisms, the documentation of their characteristics, and the collection of related information would be very useful. In this paper, we present a novel RTK detection pipeline (RTK-PRED) and the Receptor Tyrosine Kinases Database (TyReK-DB). RTK-PRED combines profile HMMs with transmembrane topology prediction to identify and classify potential RTKs. Proteins of all eukaryotic reference proteomes of the UniProt database were used as input in RTK-PRED leading to a filtered dataset of 20,478 RTKs. Based on the information collected for these RTKs from multiple databases, the relational TyReK database was created.
... The Hippo signaling pathway is mainly carried out by two activated pathways involving RTKs, the RTK/RAS/PI3K and the RTK-RAS-MAPK pathways (Azad et al., 2020). RTKs also affect cadherin cell-cell adhesion (Kaszak et al., 2020). ...
Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.
