Withaferin A inhibits proliferation of human endometrial cancer cells via transforming growth factor-β (TGF-β) signalling

Xu, Kejun; Shi, Hongyan; Du, Yongming; Ou, Jilan

doi:10.1007/s13205-021-02878-6

Cited by 15 publications

(16 citation statements)

References 25 publications

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“… 40 Conversely, a study in human endometrial cancer cells showed that withaferin A, an antiproliferative drug used in cancer treatment, suppressed proliferation, cell cycle, migration, and invasion and decreased TGF-β-related protein expression, implying that TGF-β signaling is involved in the inhibition of proliferation. 41 In this study, the KEGG database indicated that Tgfb1 was differentially regulated in relation to the cell cycle in response to ICF (Fig. 3b ).…”

Section: Discussionmentioning

confidence: 50%

Intermittent compressive force induces cell cycling and reduces apoptosis in embryoid bodies of mouse induced pluripotent stem cells

et al. 2022

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In vitro manipulation of induced pluripotent stem cells (iPSCs) by environmental factors is of great interest for three-dimensional (3D) tissue/organ induction. The effects of mechanical force depend on many factors, including force and cell type. However, information on such effects in iPSCs is lacking. The aim of this study was to identify a molecular mechanism in iPSCs responding to intermittent compressive force (ICF) by analyzing the global gene expression profile. Embryoid bodies of mouse iPSCs, attached on a tissue culture plate in 3D form, were subjected to ICF in serum-free culture medium for 24 h. Gene ontology analyses for RNA sequencing data demonstrated that genes differentially regulated by ICF were mainly associated with metabolic processes, membrane and protein binding. Topology-based analysis demonstrated that ICF induced genes in cell cycle categories and downregulated genes associated with metabolic processes. The Kyoto Encyclopedia of Genes and Genomes database revealed differentially regulated genes related to the p53 signaling pathway and cell cycle. qPCR analysis demonstrated significant upregulation of Ccnd1, Cdk6 and Ccng1. Flow cytometry showed that ICF induced cell cycle and proliferation, while reducing the number of apoptotic cells. ICF also upregulated transforming growth factor β1 (Tgfb1) at both mRNA and protein levels, and pretreatment with a TGF-β inhibitor (SB431542) prior to ICF abolished ICF-induced Ccnd1 and Cdk6 expression. Taken together, these findings show that TGF-β signaling in iPSCs enhances proliferation and decreases apoptosis in response to ICF, that could give rise to an efficient protocol to manipulate iPSCs for organoid fabrication.

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Section: Discussionmentioning

confidence: 50%

Intermittent compressive force induces cell cycling and reduces apoptosis in embryoid bodies of mouse induced pluripotent stem cells

et al. 2022

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“…Besides, in their central moieties, withaferin B contains octadecan-5-yl, whereas withaferin A contains octadec-4-en-3-one. Of note, withaferin A has been reported to be a potential anti-cancer molecule that can inhibit cell proliferation, cell migration, and cell invasion [ 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Similarly, withaferin B, bound to the FAM72A-UNG2 heterodimer, could possibly block FAM72A-UNG2 signaling pathways in cancer cells [ 26 , 29 ]; however, thus far, the biological and therapeutic properties of withaferin B remain unknown.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

Senthil¹,

Pramanik

Ekambaram³

et al. 2021

Cancers

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Family with sequence similarity 72 A (FAM72A) is a pivotal mitosis-promoting factor that is highly expressed in various types of cancer. FAM72A interacts with the uracil-DNA glycosylase UNG2 to prevent mutagenesis by eliminating uracil from DNA molecules through cleaving the N-glycosylic bond and initiating the base excision repair pathway, thus maintaining genome integrity. In the present study, we determined a specific FAM72A-UNG2 heterodimer protein interaction using molecular docking and dynamics. In addition, through in silico screening, we identified withaferin B as a molecule that can specifically prevent the FAM72A-UNG2 interaction by blocking its cell signaling pathways. Our results provide an excellent basis for possible therapeutic approaches in the clinical treatment of cancer.

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“…Although Withaferin A was found to exert anti-proliferative effects against endometrial cancer KLE cells, a reduction in normal THESCs cells post 48 h prolonged treatment was observed with a decrease in viability from 100% to 25% ( Xu et al, 2021 ). When compared, Withaferin A treatment showed greater toxicity towards endometrial cancer KLE cells than towards normal THESCs cells ( Xu et al, 2021 ).…”

Section: Withaferin a Characteristicsmentioning

confidence: 99%

“…In another study, Withaferin A treatment of human endometrial cancer KLE cells resulted in significant inhibition of cell proliferation and the IC 50 of Withaferin A against these cells was noted to be 10 μM ( Xu et al, 2021 ). Time-dependent and dose dependent anticancer activity of Withaferin A against KLE cells was observed depicting potent antiproliferative activity against the human endometrial cancer cells ( Xu et al, 2021 ). Invasive cell percentage of KLE cells decreased from 100% at 0μM to 40% at 10 μM Withaferin A treatment.…”

Section: Withaferin a Characteristicsmentioning

confidence: 99%

“…Anticancer effects of Withaferin A and its ability to modulate TGF-β signaling were investigated in human endometrial cancer where the results found G2/M cell cycle arrest and apoptosis of human KLE endometrial cancer cells ( Xu et al, 2021 ). Withaferin A was found to inhibit human endometrial cancer cell proliferation via modulation of TGF-β signaling and by inhibiting TGF-β dependent Smad2 phosphorylation ( Xu et al, 2021 ).…”

Section: Anticancer Propertiesmentioning

confidence: 99%

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Evaluating anticancer properties of Withaferin A—a potent phytochemical

Atteeq

2022

Front. Pharmacol.

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Withaferin A is a C28 steroidal lactone derived from the plant Withania somnifera, commonly known as Ashwagandha. Withaferin A has received great attention for its anticancer properties noted in cancer cells of various origins. Extracts of Withania somnifera have been used in traditional Ayurvedic and Unani Indian medicine for their various pharmacological benefits. In recent years, Withania somnifera or Ashwagandha extract has become popularized as a health supplement marketed for its stress and anxiety reducing effects. Withaferin A is one of the most studied withanolides extracted from Withania somnifera that has gained great attention for its anticancer, anti-inflammatory, metabolic, and pro-apoptotic effects. Extensive in vivo and in vitro studies have depicted Withaferin A’s interactions with key role players in cancerous activity of the cell to exert its pro-apoptotic effects. Withaferin A interactions with NF-κB, STAT, Hsp90, ER-α, p53, and TGF-β have noted inhibition in cancer cell proliferation and cell cycle arrest in G2/M stage, ultimately leading to apoptosis or cell death. This review highlights pro-apoptotic properties of Withaferin A including generation of reactive oxidative species, Par-4 activation, endoplasmic reticulum stress (ER) induction, and p53 activation. Analysis of Withaferin A’s involvement in various oncogenic pathways leading to malignant neoplasm and its pharmacologic activity in conjunction with various cancer drugs provides promising evidence in therapeutic potential of Withaferin A as a cancer treatment.

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Withaferin A inhibits proliferation of human endometrial cancer cells via transforming growth factor-β (TGF-β) signalling

Cited by 15 publications

References 25 publications

Intermittent compressive force induces cell cycling and reduces apoptosis in embryoid bodies of mouse induced pluripotent stem cells

Intermittent compressive force induces cell cycling and reduces apoptosis in embryoid bodies of mouse induced pluripotent stem cells

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

Evaluating anticancer properties of Withaferin A—a potent phytochemical

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