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Genistein inhibits EGF-induced proliferation and FOXO3 phosphorylation and translocation in colon cancer cells. (A) HT-29 cells were stimulated with EGF in presence of genistein (10, 50, 100, and 150 μM) and assayed for proliferation 48 hours later by MTS. This experiment was repeated three independent times and graphed data are mean ± sd (n = 24, *p < 0.001). (B) Genistein inhibits EGF-induced FOXO3 phosphorylation. HT-29 cells treated with EGF, with and without genistein, were examined for phosphorylated FOXO3 at Thr32. Genistein inhibits EGF induced FOXO3 phosphorylation. Immunoblots were performed three independent times and graphs represent densitometric analysis means ± sd (n = 3, *p < 0.05). (C) Genistein inhibits EGF-induced translocation of FOXO3. Immunofluorescent staining of experimental monolayers revealed that EGF-induced FOXO3 translocation from the nucleus to the cytosol was inhibited by genistein. This experiment was repeated two times in triplicate. (D) Genistein inhibits FOXO3 phosphorylation in colon cancer cells. Equal amounts of protein extracted from 70% confluent (proliferative) and 100% confluent HT-29 monolayers were separated and immunoblotted with antibodies against phosphorylated FOXO3, total FOXO3, and actin. In proliferative HT-29 cells (70% confluent), the phosphorylated form of FOXO3 is increased relative to non-proliferative cells (100% confluent). HT-29 cells (70% confluent) were incubated with genistein for 24 hours and the status of phosphorylated FOXO3 was examined. Genistein attenuates phosphorylated FOXO3 in sub-confluent HT-29 cells. These experiments were repeated three times and graphs represent densitometric analysis (n = 8, *p < 0.05).
Source publication
Soy consumption is associated with a lower incidence of colon cancer which is believed to be mediated by one of its of components, genistein. Genistein may inhibit cancer progression by inducing apoptosis or inhibiting proliferation, but mechanisms are not well understood. Epidermal growth factor (EGF)-induced proliferation of colon cancer cells pl...
Contexts in source publication
Context 1
... erative properties of genistein, exerted by targeting dif- ferent kinases of various proliferative pathways [9,[25][26][27][28] were assessed on EGF-induced proliferation in colon cancer cells. EGF-induced proliferation of HT-29 cells was inhibited by genistein ( Figure 1A), suggesting that genistein may affect the EGF pathway in colon cancer cells. We previously demonstrated that EGF-induced proliferation is mediated via loss of tumor suppressor FOXO3 activity [19]. ...Context 2
... previously demonstrated that EGF-induced proliferation is mediated via loss of tumor suppressor FOXO3 activity [19]. In the presence of genistein, EGF- induced FOXO3 phosphorylation at Thr32 (inactivation) [19] was inhibited ( Figure 1B), showing that genistein promotes FOXO3 activity. Active FOXO3 localizes to the nucleus and following phosphorylation by EGF, FOXO3 translocates to the cytosol [19]. ...Context 3
... FOXO3 localizes to the nucleus and following phosphorylation by EGF, FOXO3 translocates to the cytosol [19]. Genistein inhib- ited EGF-induced FOXO3 translocation to the cytosol, and thus FOXO3 remained in the nucleus ( Figure 1C). Moreover, the high basal level of phosphorylated FOXO3 (inactive) in sub-confluent HT-29 cells was sig- nificantly diminished by genistein ( Figure 1D), further supporting that genistein promotes FOXO3 activity in proliferative colon cancer cells regardless of EGF stimu- lation. ...Context 4
... inhib- ited EGF-induced FOXO3 translocation to the cytosol, and thus FOXO3 remained in the nucleus ( Figure 1C). Moreover, the high basal level of phosphorylated FOXO3 (inactive) in sub-confluent HT-29 cells was sig- nificantly diminished by genistein ( Figure 1D), further supporting that genistein promotes FOXO3 activity in proliferative colon cancer cells regardless of EGF stimu- lation. These data suggested that attenuation of EGF- induced proliferation by genistein is in part mediated by inhibition of FOXO3 phosphorylation (inactivation) and translocation to the cytosol in colon cancer cells (i.e. ...Similar publications
Skp2 is a component of the E3 ubiquitin ligase which promotes the ubiquitination-associated degradation of a cyclin-dependent kinase inhibitor, p27, resulting in increases in non-small cell lung cancer (NSCLC) cell growth. We recently showed that down-regulation of Sirtuin deacetylases 2 (SIRT2) in NSCLC increased cancer cell growth through suppres...
Citations
... Protective factors associated with decreased CRC incidence include diets rich in soybean, fruits, vegetables [42,43], and other bioactive compounds from plants that have demonstrated anticancer activities and can enhance chemotherapy efficacy [44]. For example, genistein from soybean [45], chlorophyll from vegetables [46], and flavonoids from fruits and vegetables [47] regulate signalling pathways involved in apoptosis, cell proliferation, inflammation, and modulation of the gut microbiome, thereby exerting protective effects against colon tumorigenesis. ...
Purpose
Carbohydrate intake has been linked to colorectal cancer (CRC) risk, with variations depending on the quantity and quality of carbohydrates consumed. This study aimed to investigate the association between carbohydrate quantity and quality, using the low-carbohydrate diet score (LCD) and carbohydrate quality index (CQI), and the risk of CRC in the Chinese population.
Methods
We conducted a case–control study in Guangzhou, China, with 2,799 CRC cases and an equal number of sex- and age-matched controls. Dietary data were collected using a validated food frequency questionnaire to derive the LCD and CQI, assessing the quantity and quality of carbohydrate intake separately. Odds ratios (OR) and 95% confidence interval (CI) for CRC risk were estimated using unconditional logistic regression models, and restricted cubic splines were used to explore potential non-linear relationships.
Results
The results demonstrated that higher adherence to the overall LCD score, plant-based LCD score, and CQI was associated with a lower risk of CRC. The adjusted ORs (95%CIs) for the highest quintile of intake in comparison with the lowest quintile were 0.76 (0.63, 0.91) for the overall LCD score, 0.61 (0.50, 0.74) for the plant-based LCD score, and 0.70 (0.58,0.84) for the CQI, respectively. However, the animal-based LCD did not show a significant association with CRC risk, with the adjusted OR (95%CI) for the highest quintile compared to the lowest being 0.98 (0.81, 1.18). Restricted cubic splines analysis showed non-linear associations of the overall LCD score, animal-based LCD score, and plant-based LCD score with CRC risk. In contrast, a linear relationship was observed between CQI and CRC risk (Pnonlinear = 0.594).
Conclusions
Our findings indicate that the overall LCD score, the plant-based LCD score, and the CQI were inversely associated with the risk of CRC.
... Both natural and synthetic ligands for ERβ have shown protective roles against CRC development. Genistein, an isoflavone from soy products, inhibits proliferation and promotes apoptosis by increasing the expression of ERβ followed by activation of various pathways in cancer cells 127 . Genistein has been effective in preventing and treating malignancies, including CRC 128 . ...
Gender disparities are evident across different types of digestive system cancers, which are typically characterized by a lower incidence and mortality rate in females compared to males. This finding suggests a potential protective role of female steroid hormones, particularly estrogen, in the development of these cancers. Estrogen is a well-known sex hormone that not only regulates the reproductive system but also exerts diverse effects on non-reproductive organs mediated through interactions with estrogen receptors (ERs), including the classic (ERα and ERβ) and non-traditional ERs [G protein-coupled estrogen receptor (GPER)]. Recent advances have contributed to our comprehension of the mechanisms underlying ERs in digestive system cancers. In this comprehensive review we summarize the current understanding of the intricate roles played by estrogen and ERs in the major types of digestive system cancers, including hepatocellular, pancreatic, esophageal, gastric, and colorectal carcinoma. Furthermore, we discuss the potential molecular mechanisms underlying ERα, ERβ, and GPER effects, and propose perspectives on innovative therapies and preventive measures targeting the pathways regulated by estrogen and ERs. The roles of estrogen and ERs in digestive system cancers are complicated and depend on the cell type and tissue involved. Additionally, deciphering the intricate roles of estrogen, ERs, and the associated signaling pathways may guide the discovery of novel and tailored therapeutic and preventive strategies for digestive system cancers, eventually improving the care and clinical outcomes for the substantial number of individuals worldwide affected by these malignancies.
... Genistein reduced the proliferation of colon cancer cells by diminishing the negative impact of epidermal growth factor (EGF) on the activity of FOXO3 [137]. The proliferation rate of HT-29 cells by genistein treatment (150 µM) was about 10% of that of the control group under EGF. ...
There have been many studies reporting that the regular consumption of fruits and vegetables is associated with reduced risks of cancer and age-related chronic diseases. Recent studies have demonstrated that reducing reactive oxygen species and inflammation by phytochemicals derived from natural sources can extend lifespans in a range of model organisms. Phytochemicals derived from fruits and vegetables have been known to display both preventative and suppressive activities against various types of cancer via in vitro and in vivo research by interfering with cellular processes critical for tumor development. The current challenge lies in creating tailored supplements containing specific phytochemicals for individual needs. Achieving this goal requires a deeper understanding of the molecular mechanisms through which phytochemicals affect human health. In this review, we examine recently (from 2010 to 2024) reported plant extracts and phytochemicals with established anti-aging and anti-cancer effects via the activation of FOXO3 transcriptional factor. Additionally, we provide an overview of the cellular and molecular mechanisms by which these molecules exert their anti-aging and anti-cancer effects in specific model systems. Lastly, we discuss the limitations of the current research approach and outline for potential future directions in this field.
... Phytoestrogens are anti-carcinogenic and are contained in beans. Genistein, a phytoestrogen, mediates a cancer promotor EGF protein, which inhibits the proliferation of HT-29 colon cancer cells [52]. Flavonoids tend to be anti-carcinogenic as they have a high folate content and cause apoptosis of colon cancer cells. ...
Introduction
Low-income countries in East Africa have a lower incidence of colorectal cancer (CRC) than high-income countries; however, the incidence has steadily increased in the last few decades. In Uganda, the extent to which genetic and environmental factors, particularly dietary factors, contribute to the aetiology of CRC is unclear. Therefore, the objective of our study was to determine the relationship between dietary factors and CRC in Uganda.
Methods
We conducted a case-control study and recruited 128 cases and 256 controls, matched for age (± 5 years) and sex. Data regarding the frequency of consumption of the dietary factors were obtained from all the participants using an interview-based questionnaire. The potential dietary risk factors and protective factors evaluated included the type and frequency of meat consumed and the type and frequency of high-fibre foods consumed. The frequency was either 4 or more times/week, 2–3 times/week, once/week or never. Conditional logistic regression analyses were used to determine the odds ratios associated with the different risk and protective factors.
Results
The median age (IQR) for the case participants was 55.5 (43-67.5) years, and that of the control participants was 54 (42–65) years. The male-to-female ratio was 1:1 for all the participants. Factors significantly associated with CRC cases included:- the consumption of boiled beef 2–3 times/week (aOR:3.24; 95% CI: 1.08–9.69; p < 0.035). Consumption of high-fibre foods, including:- millet for ≥ 4 times/week (aOR: 0.23; 95% CI: 0.09–0.62; p = 0.003)), spinach for ≥ 4 times/week (aOR:0.32; 95% CI: 0.11–0.97; p = 0.043), and potatoes 2–3 times/week (aOR: 0.30; 95% CI: 0.09–0.97; p = 0.044), were protective against CRC. Boiled cassava showed a tendency to reduce the likelihood of CRC when consumed ≥ 4 times/week (aOR:0.38; 95% CI: 0.12–1.18) however this did not reach statistical significance (p = 0.093).
Conclusions
The consumption of boiled beef increases the risk of CRC, while the intake of high-fibre foods may reduce the risk of CRC among Ugandans. We recommend nutritional educational programmes to increase public awareness regarding the protective role of a high-fibre diet and to limit the intake of cooked meat in our Ugandan population.
... This also uncovered a novel method by which genistein reduces CRC cell proliferation (Fig. 10). Qi et al. [100] demonstrated that in colon cancer cells, genistein inhibits EGF-induced FOXO3 disassociation from the p27kip1 promoter, hence Fig. 10. Genistein inhibits proliferation in CRC cells by promoting FOXO3 activity. ...
... Genistein stimulates the connection between FOXO3 and p53 and inhibits PI3K/Akt, hence increasing FOXO3 activity. Further up the line, p27kip1 expression is elevated by genistein-mediated FOXO3 activity, which encourages cell cycle arrest and suppresses proliferation [100]. Symbol show inhibitory/suppressive (⊥) effects. ...
... This study also showed that interaction between mutant tumor suppressor p53 and FOXO3 is necessary for enhanced p27kip1 expression. Qi et al. [100] showed that genistein raised wild type but not mutated p53 expression in human lung cancer cells, whereas it increased mutated p53 expression in colon cancer HT-29 cells [101][102][103][104]. Given the implication of p53 mutations on CRC development, genistein antiproliferative qualities may be linked to p53 targeting, which in turn stimulates FOXO3 action and cell cycle arrest [105,106]. According to Qi et al. [100], this study showed that genistein inhibits CRC cell development by decreasing the negative impact of EGF on tumor suppressor FOXO3 function. ...
ABSTRACT
Background: A form of cancer that affects the rectum or colon (large intestine) is called colorectal
cancer (CRC). The main risk factors for CRC include dietary, lifestyle, and environmental vari�ables. Currently natural polyphenols have demonstrated impressive anticarcinogenic capabilities.
Objective: The main objective was to provide an updated, thorough assessment of the defensive
mechanism of natural polyphenols for the global suppression of colorectal cancer. More precisely, this study aimed to analyze a set of chosen polyphenols with demonstrated safety, effectiveness,
and biochemical defense mechanism on colon cancer models in order to facilitate future research. Methods: This review was carried out with purposefully attentive and often updated scientific databases, including PubMed, Scopus, Science Direct, and Web of Science. After selecting approximately 178 potentially relevant papers based just on abstracts, 145 studies were metic�ulously reviewed and discussed.
Results: The outcomes disclosed that anti-CRC mechanisms of natural polyphenols involved the
control of several molecular and signaling pathways. Natural polyphenols have also been shown
to have the ability to limit the growth and genesis of tumors via altering the gut microbiota and
cancer stem cells. However, the biochemical uses of many natural polyphenols have remained
restricted because of their truncated water solubility and low bioavailability. In order to attain
synergistic properties it is recommended to combine the use of different natural polyphenols
because of their low bioavailability and volatility. However, the use of lipid-based nano- and
micro-carriers also may be helpful to solve these problems with efficient distribution system to
target sites.
Conclusion: In conclusion, the use of polyphenols for CRC treatment appears promising. To ascertain their efficacy, more clinical research is anticipated.
... Genistein [5,7-dihyroxy-3-(-4-hydroxyphenyl)-4H-1-benzopyran-4-one], a bioflavonoid found in soy products [1], has sparked a growing interest in oncological research due to its potential ability to modulate crucial intracellular signaling pathways in cell proliferation and survival [2,3]. Among these pathways, genistein has been indicated to modulate Wnt signaling; and has emerged as a promising therapeutic target in cancer treatment, highlighting genistein's anti-proliferative and anti-metastatic effects in various cancer types [4]. ...
... 9,14,46,47 Genistein acts as a protein tyrosine kinase (EGFR, insulin receptor) inhibitor that regulates protein phosphorylation and is effective in processes such as differentiation, angiogenesis, metastasis, and apoptosis through pathways such as Akt, NFκB, and ERK1/2. 11,48,49 In a study by Qi et al., 50 genistein inhibited EGFinduced loss of FOXO3 that led to increased p27kip1 (cell cycle inhibitor) expression activity by targeting the PI3K/Akt pathway. 50 In addition, genistein inhibited cell invasion and migration of colon cancer cells by regulating the expression of migration-associated factors and genes (MMP9, E-cadherin, β-catenin, c-Myc, and cyclin D1). ...
... 11,48,49 In a study by Qi et al., 50 genistein inhibited EGFinduced loss of FOXO3 that led to increased p27kip1 (cell cycle inhibitor) expression activity by targeting the PI3K/Akt pathway. 50 In addition, genistein inhibited cell invasion and migration of colon cancer cells by regulating the expression of migration-associated factors and genes (MMP9, E-cadherin, β-catenin, c-Myc, and cyclin D1). 51 Genistein causes DNA strand breaks and induction of apoptosis through topoisomerase inhibition, which occurs in steps such as DNA replication and recombination. ...
... In another study, the IC 50 value was 50 μM for 48 hours, showing that the effects of genistein depend on the properties of cell lines. 50,[56][57][58] The cytotoxic effects of 5-fluorouracil in colorectal cancer cells are also known. 59,60 In our study, the effects of genistein, 5-fluorouracil, and TRAIL were evaluated in SW480 and SW620 cells. ...
Objectives
Colorectal cancer is one of the most common cancers worldwide. However, surgical intervention and chemotherapy provide only limited benefits for the recovery and survival of patients. The anticarcinogenic effect of genistein has attracted attention because epidemiological studies have shown that soybean consumption is associated with a decrease in the incidence of cancer. There are limited studies on the effects of genistein in colorectal carcinoma cells. We aimed to investigate the cytotoxic, genotoxic, and apoptotic effects of genistein in SW480 and SW620 colon adenocarcinoma cells treated with 5-fluorouracil, the basis of chemotherapy, and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) ligand, the mediator of apoptosis, both alone and in combination.
Materials and Methods
Cytotoxicity and genotoxicity were determined by MTT and comet assays, respectively. The apoptotic effects were evaluated by reverse transcription-polymerase chain reaction assay, with the additional use of Annexin V FITC, mitochondrial membrane potential (MMP), caspase 3, 8, and 9 activity, and reactive oxygen species (ROS) assay kits.
Results
According to our findings, genistein, 5-fluorouracil, and TRAIL had synergistic apoptotic effects because of DR5 upregulation, ROS production, and DNA damage, which were mediated by increased caspase-8, and -9 activity and decreased MMP.
Conclusion
The applied combinations of these compounds may contribute to the resistance problem that may occur in treating colorectal cancer, with a decrease in DcR1 and XIAP genes.
... In a mechanistic study of genistein, it was revealed that Akt inhibition causes decreased telomerase enzyme activity as well as an elevated level of cell cycle progression inhibitor (i.e., p27) leading to apoptosis activation in breast cancer (Chinni et al. 2003). Similarly, genistein inactivates Akt protein in colon cancer cells via stimulation of the Foxo3 transcription factor that finally increased the p27 expression levels (Qi et al. 2011). Recently, genistein plus centchroman inhibited the phosphorylation of PI3K, NF-κB, and Akt which subsequently promoted apoptosis in breast adenocarcinoma by following events such as PARP cleavage, elevated Bax/ Bcl 2 ratio, and stimulation of caspases 3 and 9 (Kaushik et al. 2019). ...
Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies.
... In studies with colon cancer cells, soy foods have demonstrated an anti-proliferative effect on these cells. In particular, genistein has been shown to suppress colon cancer cell growth via attenuating activity of the PI3K/Akt pathway as well as affect the Wnt signaling pathway, which is important for colon tumorigenesis [81]. Though some human and animal studies have supported that soybean consumption prevents colon cancer, some have not reached the same conclusion [80]. ...
Due to the advantages of the approaches used in different disciplines in producing innovative solutions, more technologies are transferred from one discipline to another and can be used successfully. For example, while the extrusion technology used in the production of plastic can be used in the production of pasta, nowadays foodstuffs can be used just like a dye, making them shaped and layered like cement, and for this purpose, highly variable products can be produced through the software used for shaping in the machinery industry. Considering the highly variable consumer demands in the context of broad socioeconomic conditions, innovative approaches gain utmost importance in cases where conventional methods are insufficient. For example, in addition to the need to produce food with improved chewability, that is, to customize food production for a segment with a high-income level but having difficulty chewing due to advanced age, the development of alternative and practical solutions for the masses who have difficulty reaching meat protein. Proteins creates a solution requirement for two different endpoints. Thus, applying the production methods of different disciplines for innovative approaches to the points where traditional production methods cannot provide a solution in terms of improving both food supply and functional properties can enable extremely fast solutions to be produced. Therefore, some innovative and useful approaches such as mincemeat and processing of products that cannot be evaluated in meat production as steak or combining a meat alternative. Meat alternatives herbal mixture with the same meat structure and properties or processing probiotic ingredients in cheese layers are discussed with examples in this chapter.
... In studies with colon cancer cells, soy foods have demonstrated an anti-proliferative effect on these cells. In particular, genistein has been shown to suppress colon cancer cell growth via attenuating activity of the PI3K/Akt pathway as well as affect the Wnt signaling pathway, which is important for colon tumorigenesis [81]. Though some human and animal studies have supported that soybean consumption prevents colon cancer, some have not reached the same conclusion [80]. ...
Nowadays, consumers are increasingly likely to choose alternatives to cow’s milk due to several factors such as lactose intolerance, cow’s milk allergy, hypercholesterolemia prevalence and preference for vegan diets. Furthermore, meat is increasingly being criticised because of human health, environmental and animal welfare concerns. So, people tend to consume more sustainable and nutritious foods for the future and health of themselves as well as planet. To meet this customer demand, companies are also turning their attention to developing a new generation of plant-based foods. The animal source foods such as meat, milk and egg are one of the best sources of high-quality protein and micronutrients which are important for development and growth. For plant-based foods, main difficulty is to mimic the desirable flavor, appearance, mouthfeel and texture, and functionality of these products using ingredients which are completely extracted from botanical sources. Plant extracts consist various health beneficial ingredients including anti-oxidants, phenolic compounds, unsaturated fatty acids, bioactive compounds such as phytosterols and isoflavones that make plant-based foods an interesting choice. The consumption of plant-based foods can decrease the risk of cardiovascular disease, particular cancers and type 2 diabetes, retain anti-inflammation and immune activity, decrease obesity-induced metabolic dysfunction, decrease the incidence of hyperlipidemia, hyperglycemia and hypertension, improve weight loss and weight maintenance, and prevent osteoporesis, etc. In this book chapter, plant-based foods have been categorized under two headings, plant-based milk substitutes and plant-based meat substitutes. Herein, a detailed overview of the ingredients of these substitutes and their effects on human health is presented.
