EGCG inhibits CSC‐like properties through targeting miR‐485/CD44 axis in A549‐cisplatin resistant cells

Jiang, Pan; Xu, Chuyue; Chen, Lijun; Chen, Aochang; Wu, Xiaoyue; Zhou, Ming; Haq, Ijaz ul; Mariyam, Zahula; Feng, Qing

doi:10.1002/mc.22901

Cited by 46 publications

(33 citation statements)

References 38 publications

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“…CD44 was directly targeted by miR-485 in A549-cisplatin resistant lung cancer cells. CD44 was overexpressed in A549-cisplatin resistant lung cancer cells but EGCG treatment exerted repressive effects on CD44 levels by enhancing miR-485-mediated targeting of CD44 [61]. EGCG also induced regression of tumors in mice xenografted with A549-cisplatin resistant lung cancer cells.…”

Section: Tumor Suppressor Mirnasmentioning

confidence: 96%

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

Farooqi

Pinheiro

Granja

et al. 2020

Cancers

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Decades of research have enabled us to develop a better and sharper understanding of multifaceted nature of cancer. Next-generation sequencing technologies have leveraged our existing knowledge related to intra- and inter-tumor heterogeneity to the next level. Functional genomics have opened new horizons to explore deregulated signaling pathways in different cancers. Therapeutic targeting of deregulated oncogenic signaling cascades by products obtained from natural sources has shown promising results. Epigallocatechin-3-gallate (EGCG) has emerged as a distinguished chemopreventive product because of its ability to regulate a myriad of oncogenic signaling pathways. Based on its scientifically approved anticancer activity and encouraging results obtained from preclinical trials, it is also being tested in various phases of clinical trials. A series of clinical trials associated with green tea extracts and EGCG are providing clues about significant potential of EGCG to mechanistically modulate wide ranging signal transduction cascades. In this review, we comprehensively analyzed regulation of JAK/STAT, Wnt/β-catenin, TGF/SMAD, SHH/GLI, NOTCH pathways by EGCG. We also discussed most recent evidence related to the ability of EGCG to modulate non-coding RNAs in different cancers. Methylation of the genome is also a widely studied mechanism and EGCG has been shown to modulate DNA methyltransferases (DNMTs) and protein enhancer of zeste-2 (EZH2) in multiple cancers. Moreover, the use of nanoformulations to increase the bioavailability and thus efficacy of EGCG will be also addressed. Better understanding of the pleiotropic abilities of EGCG to modulate intracellular pathways along with the development of effective EGCG delivery vehicles will be helpful in getting a step closer to individualized medicines.

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Section: Tumor Suppressor Mirnasmentioning

confidence: 96%

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

Farooqi

Pinheiro

Granja

et al. 2020

Cancers

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“…EGCG was shown to affect the survival of cancer stem cells (CSCs). EGCG inhibits CSCs growth and stemness in several malignancies, such as breast [199], lung [54,200], colorectal cancer [85], osteosarcoma [14], and neuroblastoma [201].…”

Section: 67-kda Laminin Receptor Signalling Pathwaysmentioning

confidence: 99%

“…Recently, the role of EGCG in inhibiting cancer stem cells (CSC) growth and altering their features is emerging [54,95,199]. According to this literature, EGCG seems to act by downregulating CD44 expression in tumours, like non-small cell lung cancer and pancreatic cancer [200,202]. In pancreatic cancer cell lines expressing CD44, the isoform 3A of the enzyme phosphodiesterase (PDE3A) is highly expressed [202].…”

Section: 67-kda Laminin Receptor Signalling Pathwaysmentioning

confidence: 99%

Molecular Targets of Epigallocatechin—Gallate (EGCG): A Special Focus on Signal Transduction and Cancer

et al. 2018

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Green tea is a beverage that is widely consumed worldwide and is believed to exert effects on different diseases, including cancer. The major components of green tea are catechins, a family of polyphenols. Among them, epigallocatechin-gallate (EGCG) is the most abundant and biologically active. EGCG is widely studied for its anti-cancer properties. However, the cellular and molecular mechanisms explaining its action have not been completely understood, yet. EGCG is effective in vivo at micromolar concentrations, suggesting that its action is mediated by interaction with specific targets that are involved in the regulation of crucial steps of cell proliferation, survival, and metastatic spread. Recently, several proteins have been identified as EGCG direct interactors. Among them, the trans-membrane receptor 67LR has been identified as a high affinity EGCG receptor. 67LR is a master regulator of many pathways affecting cell proliferation or apoptosis, also regulating cancer stem cells (CSCs) activity. EGCG was also found to be interacting directly with Pin1, TGFR-II, and metalloproteinases (MMPs) (mainly MMP2 and MMP9), which respectively regulate EGCG-dependent inhibition of NF-kB, epithelial-mesenchimal transaction (EMT) and cellular invasion. EGCG interacts with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which modulates epigenetic changes. The bulk of this novel knowledge provides information about the mechanisms of action of EGCG and may explain its onco-suppressive function. The identification of crucial signalling pathways that are related to cancer onset and progression whose master regulators interacts with EGCG may disclose intriguing pharmacological targets, and eventually lead to novel combined treatments in which EGCG acts synergistically with known drugs.

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“…Our previously study reported that EGCG inhibited lung CSC-like properties by targeting miR-485 and RXRα ( 32 ). In addition, EGCG was found to suppress CSC-like characteristics by regulating the miR-485 and CD44 axis in A549-cisplatin resistant cells ( 33 ). The aim of the present study was to confirm the inhibitory effect of EGCG on lung CSCs and further investigate the underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin‑3‑gallate inhibits self‑renewal ability of lung cancer stem‑like cells through inhibition of CLOCK

Jiang

Zhang

et al. 2020

Int J Mol Med

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Circadian rhythm plays an important role in diverse physiological processes. Abnormal expression of circadian rhythm genes is associated with increased risk of disease, including different types of cancer. The cancer stem cell (CSC) hypothesis suggests that there is a small subset of stem-like cells within tumors that are responsible for tumor initiation. However, the biological effect of circadian rhythm on CSCs remains largely unknown. Studies have highlighted that the circadian rhythm protein CLOCK controls key aspects of various diseases. In the present study, lung cancer stem-like cells were successfully enriched using a sphere formation assay. Next, it was observed that CLOCK mRNA and protein expression levels in the A549 and H1299 sphere cells were notably increased compared with those in the corresponding parental cells. In addition, flow cytometry was performed to isolate CD133 + cells and, consistently, CLOCK expression was also found to be markedly upregulated in CD133 + lung cancer cells. Subsequently, to determine the effect of CLOCK on lung cancer stem cells in detail, CLOCK was knocked down using targeted short inhibiting RNA and the results demonstrated that the sphere-forming ability of the A549 and H1299 cell lines was reduced. In addition, CSC-like properties, including the expression of CD133, CD44, sex determining region Y-box 2, Nanog and octamer-binding transcription factor 4, were markedly decreased in the A549 and H1299 sphere cells following knockdown of CLOCK. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, has been reported to be a potential anticancer phytochemical. EGCG was found to repress CLOCK expression in A549 and H1299 sphere cells. In addition, EGCG also decreased the ratio of CD133 + cells. The Wnt/β-catenin pathway was notably inactivated by the knockdown of CLOCK in A549 and H1299 sphere cells. Subsequently, using a xenograft model, it was demonstrated that EGCG suppressed the CSC-like characteristics of lung cancer cells by targeting CLOCK. In conclusion, the present study demonstrated that EGCG inhibited the self-renewal ability of lung cancer stem-like cells by targeting CLOCK.

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EGCG inhibits CSC‐like properties through targeting miR‐485/CD44 axis in A549‐cisplatin resistant cells

Cited by 46 publications

References 38 publications

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

Molecular Targets of Epigallocatechin—Gallate (EGCG): A Special Focus on Signal Transduction and Cancer

Epigallocatechin‑3‑gallate inhibits self‑renewal ability of lung cancer stem‑like cells through inhibition of CLOCK

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