scholarly journals Inhibition of Wnt3a/FOXM1/β-Catenin Axis and Activation of GSK 3β and Caspases are Critically Involved in Apoptotic Effect of Moracin D in Breast Cancers

2018 ◽  
Author(s):  
Sung Min Hwang ◽  
Hyo-Jung Lee ◽  
Ji Hoon Jung ◽  
Deok Yong Sim ◽  
Jisung Hwang ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Beta Catenin ◽  
Breast Cancers ◽  
Mcf7 Cells ◽  
Forkhead Box M1 ◽  
Apoptosis Protein ◽  
Apoptotic Effect ◽  
Specific Protease

Though Moracin D derived from Morus alba was known to have anti-inflammatory and antioxidant activities, the underlying antitumor mechanism of Moracin D was never unveiled so far. Thus, in the recent study, the apoptotic mechanism of Moracin D was elucidated in breast cancer cells. Herein, Moracin D exerted significant cytotoxicity in MDA-MB231 and MCF7 cells. Also, Moracin D increased sub G1 population, cleaved poly (ADP-ribose) polymerase (PARP) and attenuated the expression of pro-cysteine aspartyl-specific protease (procaspase 3), c-Myc, cyclin D1, B-cell lymphoma 2 (Bcl-2),and X-linked inhibitor of apoptosis protein (XIAP) in MDA-MB231 cells. Of note, Moracin D reduced expression of Forkhead box M1 (FOXM1), β-catenin, Wnt3a, and upregulated glycogen synthase kinase 3 beta (GSK 3β) on Tyr216 along with disturbed binding of FOXM1 with β-catenin in MDA-MB-231 cells. Conversely, GSK3β inhibitor SB216763 reversed the apoptotic ability of Moracin D to reduce expression of FOXM1, β-catenin, pro-caspase3 and pro-PARP in MDA-MB-231 cells. Overall, these findings provide novel insight that Moracin D inhibits proliferation and induces apoptosis via suppression of Wnt3a/FOXM1/β-catenin signaling and activation of caspase and GSK3β

scholarly journals Inhibition of Wnt3a/FOXM1/β-Catenin Axis and Activation of GSK3β and Caspases are Critically Involved in Apoptotic Effect of Moracin D in Breast Cancers

2018 ◽  
Vol 19 (9) ◽  
pp. 2681 ◽  
Author(s):  
Sung Hwang ◽  
Hyo-Jung Lee ◽  
Ji Jung ◽  
Deok Sim ◽  
Jisung Hwang ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Adenosine Diphosphate ◽  
Breast Cancers ◽  
Forkhead Box ◽  
Forkhead Box M1 ◽  
Apoptosis Protein ◽  
Apoptotic Effect ◽  
Specific Protease

Although Moracin D derived from Morus alba was known to have anti-inflammatory and antioxidant activities, the underlying antitumor mechanism of Moracin D has not been unveiled thus far. Thus, in the recent study, the apoptotic mechanism of Moracin D was elucidated in breast cancer cells. Herein, Moracin D exerted significant cytotoxicity in MDA-MB-231 and MCF-7 cells. Furthermore, Moracin D increased sub G1 population; cleaved poly (Adenosine diphosphate (ADP-ribose)) polymerase (PARP); activated cysteine aspartyl-specific protease 3 (caspase 3); and attenuated the expression of c-Myc, cyclin D1, B-cell lymphoma 2 (Bcl-2), and X-linked inhibitor of apoptosis protein (XIAP) in MDA-MB231 cells. Of note, Moracin D reduced expression of Forkhead box M1 (FOXM1), β-catenin, Wnt3a, and upregulated glycogen synthase kinase 3 beta (GSK3β) on Tyr216 along with disturbed binding of FOXM1 with β-catenin in MDA-MB-231 cells. Conversely, GSK3β inhibitor SB216763 reversed the apoptotic ability of Moracin D to reduce expression of FOXM1, β-catenin, pro-caspase3, and pro-PARP in MDA-MB-231 cells. Overall, these findings provide novel insight that Moracin D inhibits proliferation and induces apoptosis via suppression of Wnt3a/FOXM1/β-catenin signaling and activation of caspases and GSK3β.

scholarly journals Thymoquinone and Costunolide Induce Apoptosis of Both Proliferative and Doxorubicin-Induced-Senescent Colon and Breast Cancer Cells

2021 ◽  
Vol 20 ◽  
pp. 153473542110354
Author(s):  
Ali H El-Far ◽  
Kavitha Godugu ◽  
Ahmed E. Noreldin ◽  
Amna A. Saddiq ◽  
Omar A. Almaghrabi ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Active Ingredient ◽  
Caspase 3 ◽  
Nigella Sativa ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Brdu Incorporation ◽  
Mcf7 Cells ◽  
Apoptotic Effect

Doxorubicin (Dox) induces senescence in numerous cancer cell types, but these senescent cancer cells relapse again if they are not eliminated. On this principle, we investigated the apoptotic effect of thymoquinone (TQ), the active ingredient of Nigella sativa seeds and costunolide (COS), the active ingredient of Costus speciosus, on the senescent colon (Sen-HCT116) and senescent breast (Sen-MCF7) cancer cell lines in reference to their corresponding proliferative cells to rapidly eliminate the senescent cancer cells. The senescence markers of Sen-HCT116 and Sen-MCF7 were determined by a significant decrease in bromodeoxyuridine (BrdU) incorporation and significant increases in SA-β-gal, p53, and p21 levels. Then proliferative, Sen-HCT116, and Sen-MCF7 cells were subjected to either TQ (50 µM) or COS (30 µM), the Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), caspase 3 mRNA expression and its activity were established. Results revealed that TQ significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ, MCF7 + TQ, and MCF7 + Dox5 + TQ compared with their corresponding controls. COS significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ and MCF7 + Dox5 + TQ compared with their related controls. Also, TQ and COS were significantly increased caspase 3 activity and cell proliferation of Sen-HCT116 and Sen-MCF7. The data revealed a higher sensitivity of senescent cells to TQ or COS than their corresponding proliferative cells.

Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

2019 ◽  
Vol 19 (6) ◽  
pp. 430-448 ◽  
Author(s):  
Khalid Bashir Dar ◽  
Aashiq Hussain Bhat ◽  
Shajrul Amin ◽  
Syed Anjum ◽  
Bilal Ahmad Reshi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Critical Role ◽  
Cancer Therapeutics ◽  
Adaptor Proteins ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Beta Catenin ◽  
Protein Protein Interactions ◽  
Apoptosis Protein

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

scholarly journals Antioxidant and Pro-Oxidant Capacities as Mechanisms of Photoprotection of Olive Polyphenols on UVA-Damaged Human Keratinocytes

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2153
Author(s):  
Raffaella Marina Lecci ◽  
Isabella D’Antuono ◽  
Angela Cardinali ◽  
Antonella Garbetta ◽  
Vito Linsalata ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Biological Activities ◽  
Human Keratinocytes ◽  
Ldl Oxidation ◽  
Trolox Equivalent Antioxidant Capacity ◽  
Epidermal Keratinocytes ◽  
Olive Cultivar ◽  
Human Epidermal Keratinocytes ◽  
Apoptotic Effect

A wide variety of polyphenols are reported to have considerable antioxidant and skin photoprotective effects, although the mechanisms of action are not fully known. Environmentally friendly and inexpensive sources of natural bioactive compounds, such as olive mill wastewater (OMWW), the by-product of olive-oil processing, can be considered an economic source of bioactive polyphenols, with a range of biological activities, useful as chemotherapeutic or cosmeceutical agents. Green strategies, such as the process based on membrane technologies, allow to recover active polyphenols from this complex matrix. This study aims to evaluate the antioxidant, pro-oxidant, and photoprotective effects, including the underlying action mechanism(s), of the ultra-filtered (UF) OMWW fractions, in order to substantiate their use as natural cosmeceutical ingredient. Six chemically characterized UF-OMWW fractions, from Italian and Greek olive cultivar processing, were investigated for their antioxidant activities, measured by Trolox Equivalent Antioxidant Capacity (TEAC), LDL oxidation inhibition, and ROS-quenching ability in UVA-irradiated HEKa (Human Epidermal Keratinocytes adult) cultures. The photoprotective properties of UF-OMWW were assayed as a pro-oxidant-mediated pro-apoptotic effect on the UVA-damaged HEKa cells, which can be potentially involved in the carcinogenesis process. All the UF-OMWW fractions exerted an effective antioxidant activity in vitro and in cells when administered together with UV-radiation on HEKa. A pro-oxidative and pro-apoptotic effect on the UVA-damaged HEKa cells were observed, suggesting some protective actions of polyphenol fraction on keratinocyte cell cultures.

scholarly journals Oriental Hornet (Vespa orientalis) Larval Extracts Induce Antiproliferative, Antioxidant, Anti-Inflammatory, and Anti-Migratory Effects on MCF7 Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3303
Author(s):  
Amina M. G. Zedan ◽  
Mohamed I. Sakran ◽  
Omar Bahattab ◽  
Yousef M. Hawsawi ◽  
Osama Al-Amer ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
Aqueous Extract ◽  
Antioxidant Activities ◽  
Individual Treatment ◽  
Alcoholic Extract ◽  
Anticancer Effect ◽  
Mcf7 Cells ◽  
Vespa Orientalis ◽  
Anti Inflammatory

The use of insects as a feasible and useful natural product resource is a novel and promising option in alternative medicine. Several components from insects and their larvae have been found to inhibit molecular pathways in different stages of cancer. This study aimed to analyze the effect of aqueous and alcoholic extracts of Vespa orientalis larvae on breast cancer MCF7 cells and investigate the underlying mechanisms. Our results showed that individual treatment with 5% aqueous or alcoholic larval extract inhibited MCF7 proliferation but had no cytotoxic effect on normal Vero cells. The anticancer effect was mediated through (1) induction of apoptosis, as indicated by increased expression of apoptotic genes (Bax, caspase3, and p53) and decreased expression of the anti-apoptotic gene Bcl2; (2) suppression of intracellular reactive oxygen species; (3) elevation of antioxidant enzymes (CAT, SOD, and GPx) and upregulation of the antioxidant regulator Nrf2 and its downstream target HO-1; (4) inhibition of migration as revealed by in vitro wound healing assay and downregulation of the migration-related gene MMP9 and upregulation of the anti-migratory gene TIMP1; and (5) downregulation of inflammation-related genes (NFκB and IL8). The aqueous extract exhibited the best anticancer effect with higher antioxidant activities but lower anti-inflammatory properties than the alcoholic extract. HPLC analysis revealed the presence of several flavonoids and phenolic compounds with highest concentrations for resveratrol and naringenin in aqueous extract and rosmarinic acid in alcoholic extract. This is the first report to explain the intracellular pathway by which flavonoids and phenolic compounds-rich extracts of Vespa orientalis larvae could induce MCF7 cell viability loss through the initiation of apoptosis, activation of antioxidants, and inhibition of migration and inflammation. Therefore, these extracts could be used as adjuvants for anticancer drugs and as antioxidant and anti-inflammatory agents.

scholarly journals Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

2021 ◽  
Vol 8 ◽  
Author(s):  
Mingjuan Deng ◽  
Xingqi Li ◽  
Weiwei Li ◽  
Jiahui Gong ◽  
Xiaoying Zhang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Short Chain Fatty Acids ◽  
Uremic Toxins ◽  
Short Chain ◽  
Liver Carcinoma ◽  
Apoptosis Protein ◽  
Induced Apoptosis ◽  
Chain Fatty Acids

Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 μM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 μM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.

Maternal beta-catenin establishes a ‘dorsal signal’ in early Xenopus embryos

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 2987-2996 ◽  
Author(s):  
C. Wylie ◽  
M. Kofron ◽  
C. Payne ◽  
R. Anderson ◽  
M. Hosobuchi ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Axis Formation ◽  
Beta Catenin ◽  
Cell Stage ◽  
Midblastula Transition ◽  
Xenopus Embryos ◽  
Ability To Act ◽  
Zygotic Transcription ◽  
Spatial Terms ◽  
Marginal Zones

In previous work, we demonstrated that maternally encoded beta-catenin, the vertebrate homolog of armadillo, is required for formation of dorsal axial structures in early Xenopus embryos (Heasman, J., Crawford, A., Goldstone, K., Garner-Hamrick, P., Gumbiner, B., Kintner, C., Yoshida-Noro, C. and Wylie, C. (1994). Cell 79, 791–803). Here we investigated, firstly, the role(s) of beta-catenin in spatial terms, in different regions of the embryo, by injecting beta-catenin mRNA into individual blastomeres of beta-catenin-depleted embryos at the 32 cell stage. The results indicate that beta-catenin can rescue the dorsal axial structures in a non-cell-autonomous way and without changing the fates of the injected cells. This suggests that cells overexpressing beta-catenin send a ‘dorsal signal’ to other cells. This was confirmed by showing that beta-catenin overexpressing animal caps did not cause wild-type caps to form mesoderm, but did cause isolated beta-catenin-deficient marginal zones to form dorsal mesoderm. Furthermore beta-catenin-deficient vegetal masses treated with overexpressing caps regained their ability to act as Nieuwkoop Centers. Secondly, we studied the temporal activity of beta-catenin. We showed that zygotic transcription of beta-catenin starts after the midblastula transition (MBT), but does not rescue dorsal axial structures. We further demonstrated that the vegetal mass does not release a dorsal signal until after the onset of transcription, at the midblastula stage, suggesting that maternal beta-catenin protein is required at or before this time. Thirdly we investigated where, in relationship to other gene products known to be active in axis formation, beta-catenin is placed. We find that BVg1, bFGF, tBR (the truncated form of BMP2/4R), siamois and noggin activities are all downstream of beta-catenin, as shown by the fact that injection of their mRNAs rescues the effect of depleting maternally encoded beta-catenin. Interference with the action of glycogen synthase kinase (GSK), a vertebrate homolog of the Drosophila gene product, zeste white 3 kinase, does not rescue the effect, suggesting that it is upstream.

scholarly journals Enhancement of paclitaxel-induced breast cancer cell death via the glycogen synthase kinase-3β-mediated B-cell lymphoma 2 regulation

BMB Reports ◽  
2016 ◽  
Vol 49 (1) ◽  
pp. 51-56 ◽  
Author(s):  
Kyung Tae Noh ◽  
Gil Sun Cha ◽  
Tae Heung Kang ◽  
Joon Cho ◽  
In Duk Jung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
B Cell ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cell Lymphoma ◽  
Glycogen Synthase ◽  
B Cell Lymphoma ◽  
Glycogen Synthase Kinase 3Β ◽  
Cancer Cell Death

scholarly journals Antioxidant, Antiproliferative and Apoptosis-Inducing Efficacy of Fractions from Cassia fistula L. Leaves

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 173 ◽  
Author(s):  
Sandeep Kaur ◽  
Ajay Kumar ◽  
Sharad Thakur ◽  
Kapil Kumar ◽  
Ritika Sharma ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Apoptotic Cell ◽  
Radical Scavenging ◽  
Cation Radical ◽  
Reducing Power ◽  
B Cell Lymphoma ◽  
Expression Level ◽  
Cassia Fistula ◽  
Nitric Oxide Radical ◽  
Mitochondrial Membrane Depolarization

Cassia fistula L. is a highly admirable traditional medicinal plant used for the treatment of various diseases and disorders. The present study was performed to divulge the antioxidant, antiproliferative, and apoptosis-inducing efficacy of fractions from C. fistula leaves. The hexane (CaLH fraction), chloroform (CaLC fraction), ethyl acetate (CaLE fraction), n-butanol (CaLB fraction), and aqueous (CaLA fraction) were sequentially fractionated from 80% methanolic (CaLM extract) of C. fistula leaves. The CaLE fraction was fractionated using column chromatography to yield a pure compound, which was characterized as Epiafzelechin (CFL1) based on 1H, 13C, and DEPT135 NMR. Among these fractions, CaLE and isolated CFL1 fractions exhibited an effective antioxidant potential in Ferric ion reducing power, (2,2’-azino-bis (3-ethylbenzothiazoline -6-sulfonic acid)) cation radical scavenging, and nitric oxide radical scavenging assays. Epiafzelechin was investigated for its antiproliferative effects against MG-63 (osteosarcoma), IMR-32 (neuroblastoma), and PC-3 (prostate adenocarcinoma), and was found to inhibit cell proliferation with a GI50 value of 8.73, 9.15, and 11.8 μM respectively. MG-63 cells underwent apoptotic cell death on treatment with Epiafzelechin as the cells showed the formation of apoptotic bodies, enhanced reactive oxygen species (ROS) generation, mitochondrial membrane depolarization along with an increase in early apoptotic cell population analyzed using Annexin V-FITC/PI double staining assay. Cells showed cell cycle arrest at the G0/G1 phase accompanied by a downregulation in the expression levels of p-Akt (Protein kinase B), p-GSK-3β (Glycogen synthase kinase-3 beta), and Bcl-xl (B-cell lymphoma-extra large) proteins. RT-PCR (Real time-polymerase chain reaction) analysis revealed downregulation in the gene expression level of β-catenin and CDK2 (cyclin-dependent kinases-2) while it upregulated the expression level of caspase-8 and p53 genes in MG-63 cells.

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