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Epidermal growth factor receptor (EGFR) and its downstream signaling proteins. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; Akt, protein kinase B; P, phosphorylation. Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.
Source publication
Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-?B supp...
Contexts in source publication
Context 1
... is activated by some ligands including epidermal growth factor (EGF), transforming growth factor-α, heparin-binding EGF, and amphiregulin. Ligand binding to the extracellular domain of EGFR induces a conformational change in the intracellular cytoplasmic domain, which promotes homodimerization or heterodimerization with the other ErbB family members, leading to the autophosphorylation of tyrosine residues and phosphorylation and the activation of downstream signaling pathways ( Figure 3) [45]. These pathways include Ras/Raf/MAPK, phospholipase C/phosphatidylinositol 3-kinase (PI3K)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) [46]. ...
Context 2
... is activated by some ligands including epidermal growth factor (EGF), transforming growth factor-α, heparin-binding EGF, and amphiregulin. Ligand binding to the extracellular domain of EGFR induces a conformational change in the intracellular cytoplasmic domain, which promotes homodimerization or heterodimerization with the other ErbB family members, leading to the autophosphorylation of tyrosine residues and phosphorylation and the activation of downstream signaling pathways (Figure 3) [45]. These pathways include Ras/Raf/MAPK, phospholipase C/phosphatidylinositol 3-kinase (PI3K)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) [46]. ...
Context 3
... et al. [50] examined the effect of dietary supplementation with T3 extracts from annatto seeds (10% γ-and 90% δ-T3 mixture) on the spontaneous development of mammary tumors in ErbB2 transgenic mice. Oral administration of Figure 3. Epidermal growth factor receptor (EGFR) and its downstream signaling proteins. ...
Citations
... The nuclear factor binding of light peptide gene enhancers generates inactive complexes and is in an inhibitory state in the basic state of NF-kB and B-cells inhibitor (IkB) (70). Phosphorylation of inhibitory-kB kinases (IKKs) by numerous kinases, such as AKT, mTOR, as well as mitogen-activated protein kinase (MAPK), lead to the activation of NF-kB (71)(72)(73). The transcriptional activity of NF-kB can be regulated by the RAS oncoprotein through its targeting of the transactivation domain of the NF-kB p65 subunit. ...
Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.
... It is activated via canonical (via tumor necrosis factor receptor, or TNFR) and noncanonical (via CD40) pathways [107]. However, many studies have pointed out the activation of NF-κB by the PI3K-AKT pathway [106][107][108][109][110]. ...
Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in clinics, the majority of these approaches seem to combine molecularly targeted drugs with chemotherapeutic agents. In this manuscript, we start by analyzing the list of FDA-approved molecularly targeted drugs for breast cancer to evaluate where molecular targeting stands in breast cancer treatment today. We will then provide an overview of other options currently under clinical trial or being investigated in pre-clinical studies.
... 22,23 The cytotoxic effects of T3 against cancer cells are triggered via activation of various intracellular signalling pathways such as activation of apoptosis (programmed cell death type I), autophagy (programmed cell death type II), regulation of cell cycle through inhibiting cell cycle progression through cyclin kinase-dependent (CDK), and cyclin D1, and suppression of angiogenesis. Furthermore, T3, may synergize with chemotherapeutic drugs such as statins, 24 celecoxib 25 and tamoxifen, 26,27 to augment their efficacy. Combinations of T3 and natural dietary compounds such as ferulic acid (FA) or jerantinine was reported to induce higher anticancer effects. ...
Background: The increasing number of cancer cases requires developing newer approaches to treat this disease. One approach uses natural compounds with known anticancer effects, such as tocotrienols. Many cell-based and animal-model studies found that tocotrienols possess potent anticancer activities. However, the exact molecular regulatory mechanism through which tocotrienols exert anticancer actions remains unclear.
Methods: This scoping review analysed data from original research articles reporting on the anticancer effects of tocotrienols on human cancer cell lines published in the last seven years (January 2015 and September 2021) using a systematic scoping review approach. From the initial 619 research papers [ProQuest (n= 61), PubMed (n= 84), Embase (n = 148), Ovid Medline (n =53), Scopus (n = 137), Web of Science (n =136)] identified using pre-defined keywords, only 37 articles met the inclusion and exclusion criteria for this review. Human cancers commonly studied in the 37 research articles include breast, lung, prostate and colorectal cancer cell lines.
Results: The analysis showed that exposing human cancer cell lines to tocotrienols triggered common anticancer mechanisms such as activation of apoptosis and inhibition of proliferation, angiogenesis and cell migration through regulation of key regulatory genes and proteins involved in these pathways.
Conclusions: The findings show that tocotrienols regulate a number of biomarkers that induce cell death and regulate cell cycle in various types of human cancer cells. Further targeted studies are required to map the definite pathways by which T3 exerts their action and to better understand the cellular actions and the regulatory pathways.
... EGF stimulates several intracellular signaling pathways, such as phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways, to mediate cancer cell proliferation and metastasis [30]. To explore whether MFI2 in uences the downstream signaling of EGF, the phosphorylation of focal adhesion kinase (FAK), proto-oncogene tyrosine-protein kinase Src (Src) and Akt serine/threonine kinase (Akt) were evaluated in MFI2-knockdown OSCC cell lines. ...
Oral squamous cell carcinoma (OSCC) is the predominant histological type of the head and neck squamous cell carcinoma (HNSCC). By comparing the differentially expressed genes (DEGs) in OSCC-TCGA patients with copy number variations (CNVs) that we identify in OSCC-OncoScan dataset, we herein identified 37 dysregulated candidate genes. Among these potential candidate genes, 26 have been previously reported as dysregulated proteins or genes in HNSCC. Among 11 novel candidates, the overall survival analysis revealed that melanotransferrin (MFI2) is the most significant prognostic molecular in OSCC-TCGA patients. Another independent Taiwanese cohort confirmed that higher MFI2 transcript levels were significantly associated with poor prognosis. Mechanistically, we found that knockdown of MFI2 reduced cell viability, migration and invasion via modulating EGF/FAK signaling in OSCC cells. Collectively, our results support a mechanistic understanding of a novel role for MFI2 in promoting cell invasiveness in OSCC.
... erefore, this finding indicates that other action mechanisms may contribute to the efficacy of the HDS-1 extract beyond bioenhancers for paclitaxel. According to previous findings, two possibilities are posed as follow: Taxus-derived taxane compounds may contribute to the in vivo anti-cancer effect due to the cytotoxicity property [57], or flavonoids or lignoids may exert a synergistic effect to enhance PTX's efficacy [58,59]]. e latter hypothesis is confirmed by the MTT assay in our investigation, and we find that HDS-2 (flavonoids) and HDS-3 (lignoids) exert a synergistic effect with paclitaxel toward A549 growth in vitro. e action mechanism of this synergism is assumed to be associated with augmenting the vulnerability of cancer cells to PTXinduced programmed cell death (PCD). ...
Taxus yunnanensis is a paclitaxel-containing herb with traditional usage in cancer treatment, and its extract possesses great oral bioavailability of paclitaxel. However, it is elusive whether paclitaxel-containing extract (HDS-1) can exert anti-tumor effect through oral administration and how other components contribute to its efficacy. Therefore, we investigate the oral-route anti-tumor effect of HDS-1 in A549-bearing mice. HDS-1-derived flavonoids (HDS-2) and lignoids (HDS-3) are hypothesized to contribute to HDS-1’s efficacy, and their effects of enhancing enterocytic absorption and cytotoxicity of paclitaxel are validated in 2 permeability experiments and apoptosis-related assay, respectively. In vivo, A549 growth is significantly inhibited by 86.1 ± 12.94% ( P < 0.01 ) at 600 mg/kg of HDS-1 and 65.7 ± 38.71% ( P < 0.01 ) at 200 mg/kg. HDS-2 and HDS-3 significantly reduce the efflux ratio of paclitaxel to 2.33 and 3.70, respectively, in Caco-2 permeability experiment and reduce paclitaxel reflux in MDCK-MDR1 experiment. Furthermore, HDS-2 and HDS-3 potentiated paclitaxel-induced cytotoxicity by 19.1–22.45% ( P < 0.05 ) and 10.52–18.03% ( P < 0.05 ), respectively, inhibited the expression of cyclinB1, Bcl-2, and pMCL-1, and increased the percentage of necrosis cell in the condition of paclitaxel exposure. Conclusively, paclitaxel-containing extracts exert anti-cancer effects through oral administration, and flavonoid and lignoids contribute to its anti-cancer effect through simultaneously improving enterocytic absorption of paclitaxel and the cytotoxic effect of paclitaxel.
... In the case of SOCS3 [79], it counteracted Stat3-dependent keratinocyte migration after being stimulated by HGF (Figure 2). In the case of EGFR, SOCS3 is involved in the regulation of IL-6/Jak/Stat signaling, attenuating the EGF signal [78,80]. ...
Solid tumors, despite being hypervascularized, are hypoxic. This is due to the imbalance that exists between the inputs of the blood vessels that supply nutrients and O2 and that remove metabolic waste products, on one side; and the demands of the tumor cells that are part of the neoplasm that is forming, on the other. From this perspective, we briefly review the sequence of morphological events that occur during neo-angiogenesis; what chemical mediators are involved in this process; and we emphasize how the IL-6/Jak/Stat signaling pathway is involved in the control of these mediators. At the same time, we review how estrogens intervene in this control procedure, and how it opens the door to understanding the mechanism of action of these mediators. This would make it possible to propose alternative treatments, which can be added to the conventional ones, and which would exploit the findings described here in the search for new antitumor therapies.
... In addition, EGFR is also able to mobilize the PI3K/Akt/mTOR, p53, Ras/MAPK, and NFKB pathways to regulate cell proliferation/growth, amino acid metabolism, cell survival/apoptosis, and cell morphology/motility. In addition, EGFR is known to induce the nuclear factor NFKB via PIK/Akt and MAPK signalling to regulate the immune system and associated inflammation processes, as well as angiogenesis [45]. In this context, our results showed a significant impact of acute ingestion of golden berry fruit on EGFR. ...
Purpose:
Golden berry (Physalis peruviana L.) is an exotic fruit exported from Colombia to different countries around the world. A review of the literature tends to demonstrate a hypoglycaemic effect with an improvement in insulin sensitivity after oral ingestion of fruit extracts in animal models. However, little is known about their potential effects in humans, and very little is known about the mechanisms involved. This study aimed at identifying discriminant metabolites after acute and chronic intake of golden berry.
Method:
An untargeted metabolomics strategy using high-performance chemical isotope-labelling LC-MS was applied. The blood samples of eighteen healthy adults were analysed at baseline, at 6 h after the intake of 250 g of golden berry (acute intervention), and after 19 days of daily consumption of 150 g (medium-term intervention).
Results:
Forty-nine and 36 discriminant metabolites were identified with high confidence, respectively, after the acute and medium-term interventions. Taking into account up- and downregulated metabolites, three biological networks mainly involving insulin, epidermal growth factor receptor (EGFR), and the phosphatidylinositol 3-kinase pathway (PI3K/Akt/mTOR) were identified.
Conclusions:
The biological intracellular networks identified are highly interconnected with the insulin signalling pathway, showing that berry intake may be associated with insulin signalling, which could reduce some risk factors related to metabolic syndrome. Primary registry of WHO.
... However, γ-tocopherol was shown to be the most abundant tocol in seed oils from muscadine grape cultivars (Zhao, Yagiz, Xu, Fang, & Marshall, 2017). αT assimilation is facilitated by αT transfer protein, which has a high binding affinity for αT and low affinity for non-αT congeners; thus, excessive intake of αT may reduce the absorption of non-αT forms of vitamin E (Eitsuka, Tatewaki, Nishida, Nakagawa, & Miyazawa, 2016;Fu, Che, Tan, & Teng, 2014). Absolute and relative amounts of tocotrienol in grape seed oils are significantly higher compared to other edible oils (Shinangawa et al., 2015;Zhao et al., 2017), thus accounting for high levels of bioavailability. ...
Background
The grape seed is one of the most valuable constituents of grape pomace, a by-product generated during winemaking. Using grape seed as a raw material to develop valuable products will contribute to the recycling and reuse of grape pomace, as well as to the sustainable development of the wine industry. The grape seed oil (GSO) is rich in bioactive compounds with various health-promoting properties and has great potential application in the pharmaceutical, cosmetic, and food industry.
Scope and approach
In this review, we first elaborate on the processing technologies of GSO in terms of requirements for raw materials, current extractive technologies, and oil stability. In the second part, we summarize the characteristics of GSO phytochemical compounds, such as fatty acids, phytosterols, vitamin E, and phenols. Finally, we focus on recent studies related to the GSO biological activities, including antioxidant, anti-inflammatory, and metabolic disease alleviation. In addition, the latest developments of GSO products and their derived foods are also illustrated concisely.
Key findings and conclusions
For the product design of GSO, the key may be to fully exploit and utilize the inherent characteristics of grape seed to produce functional oil with high phenol content, which requires further improvements in the extraction and storage strategy of GSO, as well as increasing the lipid solubility of phenolic compounds. In terms of technology, designing more environmentally friendly, efficient, and low-cost processes and equipment for making GSO is also a trend. Concerning physiological activity, studies combining lipidomics, proteomics, metabolomics, and nutriomics may provide further insights into the mechanisms of the health benefits induced by GSO.
... While extensive research from in vitro studies to clinical trials has been conducted with tocopherols, the same cannot be said for tocotrienols. To a lesser extent, the mechanism of action of tocotrienols has been investigated in various types of cancer cells [16,17,21,44,45] as well as in breast cancer cell lines specifically [18]. For example, Alawin et al. demonstrated that γ-tocotrienol accumulates in lipid rafts, suppressing human epidermal growth factor receptor 2 (HER2) signaling in SKBR3 and BT474 human breast cancer cell lines [46]. ...
... Additionally, some studies have suggested that tocotrienols have chemosensitizing potential. In breast cancer cells, the chemosensitizing actions of tocotrienols in combination with chemotherapeutic drugs including gefitinib, erlotinib, and celecoxib were observed [39,44]. In colorectal, gastric, liver, oral, and prostate cancer cell lines, synergistic anti-cancer activities were observed with tocotrienols and drugs commonly used in breast cancer treatment-docetaxel, paclitaxel, doxorubicin, or capecitabine [39]. ...
In the past few years, breast cancer has become the most prevalent type of cancer. The majority of patients receive combinatorial chemotherapy treatments, which may result in increased risk of developing drug resistance, a reduced quality of life, and substantial side effects. Treatment modalities that could lessen the physical toll of standard treatments or act in synergy with chemotherapeutic treatments would benefit women worldwide. Research into tocotrienols has thus far demonstrated their potential to be such an agent, with tocotrienols surpassing the pharmacological potential of tocopherols. Further research using in vitro and preclinical breast cancer models to support clinical trials is needed. This review uses bibliometric analysis to highlight this gap in research and summarizes the current and future landscape of tocotrienols as an anti-breast cancer agent.
... Therefore, targeting these angiogenic factors seemed to be the most rational intervention to combat tumour growth [220,221]. Several trials [222][223][224] have shown the effectiveness of tocotrienol in inhibiting angiogenesis in various cancers, with the process illustrated in Figure 7 below [225]. ...
